Methods for lowering blood pressure with a dihydropyridine-type calcium channel blocker pharmaceutical composition

ABSTRACT

A method is provided for lowering blood pressure in a subject in need thereof by administering a dihydropyridine-type calcium channel blocker pharmaceutical composition to a subject qualified for over-the-counter access to the dihydropyridine-type calcium channel blocker pharmaceutical composition. In some embodiments, the dihydropyridine-type calcium channel blocker pharmaceutical composition includes isradipine, nifedipine, or nisoldipine. In some embodiments, the dihydropyridine-type calcium channel blocker pharmaceutical composition includes 3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate or a pharmaceutically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.16/440,319 filed Jun. 13, 2019, which claims priority to U.S.Provisional Patent Application Ser. No. 62/685,209, filed Jun. 14, 2018,both of which are hereby incorporated by reference in their entireties.

TECHNICAL FIELD

The present disclosure relates generally to methods for lowering bloodpressure, e.g., thereby treating and/or preventing heart disease, byadministering an over-the-counter dihydropyridine-type calcium channelblocker pharmaceutical composition to a subject in need thereof, who hasbeen qualified for over-the-counter access to the composition.

BACKGROUND

Hypertension, e.g., high blood pressure, is the leading cause of deathworldwide and the second-leading cause of preventable death in theUnited States. Roberts, N., et al., Emitro Health, “Feeling the Pressureof New Guidelines for the Treatment of Hypertension,” (2017). As of2014, according to the CDC, 1 in 3 adults in the U.S. was inflicted withhigh blood pressure and about 46% of those individuals did not havetheir blood pressure under control. Merai R., et al., MMWR Morb MortalWkly Rep, 65:1261-1264 (2016). Of the approximately 35 million U.S.citizens that do not have their blood pressure under control, about 20%are aware that they have high blood pressure, yet are not being treated.Id. The CDC estimates that $49 billion is spent annually in direct andindirect medical expenses relating to uncontrolled hypertension. Id.

Fortunately, hypertension can be managed, for example, usingdihydropyridine-type calcium channel blockers, which are wellestablished prescription pharmaceuticals used to lower blood pressure,thereby preventing heart disease. For instance, the efficacy ofamlodipine, which was first approved in the U.S. for the treatment ofhypertension in 1992, to lower blood pressure has been demonstrated inat least 15 double-blind, placebo-controlled, randomized studies.However, access to dihydropyridine-type calcium channel blockers isrestricted by the requirement for a prescription. Unfortunately,long-term trends demonstrate many people avoid prescription medications,including dihydropyridine-type calcium channel blockers.

One approach to making dihydropyridine-type calcium channel blockersmore accessible is to make them available without a prescription, e.g.,over the counter (“OTC”). There are a variety of health benefits derivedfrom switching a drug from prescription to OTC including, but notlimited to, generating wider availably to therapies, providing a greaternumber of therapeutic approaches, providing direct and rapid access totreatments, providing patients with an active role in their own healthcare, and allowing patients to become self-reliant in preventing andrelieving minor symptoms or conditions (World Health Organization, 2000,“Guidelines for the Regulatory Assessment of Medicinal Products for usein Self-Medication,” Print). Given the large number of individuals withuncontrolled high blood pressure, providing access to OTCdihydropyridine-type calcium channel blockers could provide significantsocietal health benefits.

However, switching distribution of a pharmaceutical fromprescription-only to OTC creates a significant risk that the patientpopulation will be unable to appropriately self-select themselves forsafe use of the pharmaceutical use and then self-medicate using the drugin a responsible manner. The manifestations embodied within theseconcerns include incorrect self-diagnosis, incorrect drug-qualification,unrecognized drug-drug interactions (DDI), unanticipated adverse drugreactions and/or side-effects, improper dosing and/or administration,masking of a disease, addiction, inappropriate drug dependency,substance abuse, and patient delay in seeking necessary medicalattention. Ruiz et al., Current Drug Safety, 5(4):315 (2010).

In order to ensure the safety of OTC distribution ofdihydropyridine-type calcium channel blockers, prospective patients musteffectively self-select themselves for the drug. Recent studies,however, found that many prospective patients do not pay consistentattention to guidelines printed on the packaging of OTC drugs, to ensuresafe and responsible use. PR Newswire Association, “Americans Should PayMore Attention to Over-the-Counter (OTC) medicine Labels According toNew Survey,” Oct. 15 (2015) (citing McNeil Consumer Healthcareresearch). According to these studies, 40% of prospective patientsconsider the directions as just guidelines and 80% of patients do notre-read the label of an OTC medicine they have used before. Even moretroubling, only 58% of men surveyed found it very important to payattention to restrictions on an OTC label.

Currently, there are two regulatory pathways for legal marketing of anOTC drug in the United States. In the first pathway, marketing occurs incompliance with an OTC drug monograph, that sets regulatory standardsfor non-prescription drugs that are not covered by human drugapplications, e.g., a New Drug Application (NDA) or Abbreviated New DrugApplication (ANDA). An OTC monograph is created as a result of a threephase OTC drug review by the FDA. In phase I of the review, an advisoryreview panel determines whether ingredients in the proposed OTCcomposition could be generally recognized as safe and effective for usein self-treatment. In the second pathway, marketing occurs under theauthority of an approved product-specific new drug application (NDA), oran abbreviated new drug application (ANDA). In order to support anover-the-counter label for a drug for which regulatory approval is beingsought through an NDA, a consumer research study is required to assessthe consumer's ability to select and deselect themselves as appropriateusers of the drug, based on the proposed labeling for the drug. Oliver,A., Regulatory Rapporteur, 10(3):4-9 (2013), which is incorporated byreference herein.

However, attempts at switching distribution of cardiovascular drugshaving potentially far-reaching benefits for societal health, fromprescription-only to an OTC model, have repeatedly failed, in large partdue to concerns over inappropriate patient selection and medication.Possibly the best documented cases relate to statins used to treat highcholesterol.

For instance, Merck has had at least three applications for sale of overthe counter lovastatin rejected by the FDA, in 2000, 2005, and 2007. In2005, their proposal to permit over the counter sales of lovastatin wasrejected by an expert advisory panel at the FDA in 2005. The panel wasconcerned by a marketing study performed to support the proposal inwhich approximately one third of 3316 customers who were offered thedrug over the counter decided they would purchase the drug. Afterreviewing the data, the panel concluded that 45% of the purchases wouldhave been inappropriate for a variety of reasons, including the age ofthe subject, the subject's lack of knowledge about their condition, andcontraindications associated with their condition. Dyer O., BMJ,330(7484):164 (2005). In 2007, the board again concluded that theability of consumers to appropriately self-select and to adequatelycomply with chronic MEVACOR® therapy without the intervention of aphysician had not been demonstrated. Division of Metabolic and EndocrineDrug Products, 2005, “NDA 21-213 Non-prescription MEVACOR® 20 mg JointAdvisory Committee Meeting.”

Similarly, Pfizer announced in 2011 its intention to switch LIPITOR®from prescription-only to OTC status. Sett OTC bulletin, 16 Nov. 2011,page 7. However, they abandoned their attempt in 2014 when a phase 3“actual use” trial, intended to simulate the OTC use of LIPITOR®(atorvastatin calcium) 10 mg, failed to meet its primary objectives onthe basis that patient compliance with the direction to check theirlow-density lipoprotein cholesterol (LDL-C) level and, after checkingtheir LDL-C level, take appropriate action based on their test resultswas unsatisfactory. Pfizer Inc., “Pfizer Reports Second-Quarter 2015Results,” (2015).

In fact, in the nearly two decades since Bristol-Myers Squibb and Merck& Co first failed in their attempts to switch PRAVACHOL® and lovastatin,respectively, to OTC, a statin has never been granted OTC status in theUnited States. This is despite that nearly 40 million adults in the U.S.who are eligible for cholesterol-lowering medications, under the currentguidelines, are not taking anything.

The information disclosed in this Background section is only forenhancement of understanding of the general background of the inventionand should not be taken as an acknowledgment or any form of suggestionthat this information forms the prior art already known to a personskilled in the art.

SUMMARY

Given the above background, what is needed in the art are systems andmethods for qualifying a human subject for delivery of adihydropyridine-type calcium channel blocker pharmaceutical compositionover-the-counter to lower blood pressure, e.g., thereby, treating orpreventing heart disease.

The present disclosure addresses the need in the art for systems andmethods configured for qualifying a human subject for over-the-counterdelivery of a dihydropyridine-type calcium channel blockerpharmaceutical composition (e.g., amlodipine) in order to treat orprevent heart disease, e.g., by lowering blood pressure. In the presentdisclosure, systems and methods are provided for over-the-counterdelivery of a dihydropyridine-type calcium channel blockerpharmaceutical composition to a subject. Survey results from the subjectare run against a first plurality of filters. When a filter in the firstplurality is fired, the subject is deemed not qualified for delivery ofthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition. The survey results are also run against a second pluralityof filters. When a respective filter in the second plurality is fired,the subject is provided with a corresponding warning. The methodproceeds to a fulfillment process when no filter in the first pluralityis fired and the subject has acknowledged each warning associated witheach fired filter in the second plurality of filters. The fulfillmentprocess stores the composition order, communicates a drug facts labelfor the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition to the subject, and authorizes, upon subject confirmationthat the label has been read, provision of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject.

Accordingly, one aspect of the present disclosure provides a method forqualifying a subject for over-the-counter delivery of adihydropyridine-type calcium channel blocker pharmaceutical compositionin order to lower the blood pressure of the subject. The method includesconducting a first survey of the subject in order to obtain a variety ofsurvey results. In some embodiments, the survey results include one ormore of: whether the subject is pregnant, breastfeeding, or planning tobecome pregnant, whether the subject is already taking anotherdihydropyridine-type calcium channel blocker, the current systolic bloodpressure of the subject, the current diastolic blood pressure of thesubject, whether the subject has ever had an atheroscleroticcardiovascular event or had a heart procedure, the gender of thesubject, the age of the subject, the subject's race, whether the subjectis taking any blood pressure medications, the diabetes status of thesubject, whether the subject smokes, the total cholesterol level of thesubject, the high-density lipoprotein (HDL) cholesterol level of thesubject, whether the subject has ever had a liver problem, and whetherthe subject is taking a medication that interacts (e.g., apharmacokinetic interaction and/or a pharmacodynamic interaction) withthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition.

The method also includes running all or a portion of the survey resultsagainst a first plurality of filters of a first category class. When arespective filter in the first plurality of filters is fired, thesubject is deemed not qualified for delivery of the dihydropyridine-typecalcium channel blocker pharmaceutical composition. The method is thenterminated accordingly without delivery of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject. Insome embodiments, the first plurality of filters includes one or more ofa first pregnancy filter, a dihydropyridine medication filter, a firstblood pressure filter, an age filter, and a pooled cohort equationfilter.

The method also includes running all or a portion of the survey resultsagainst a second plurality of filters of a second category class. When arespective filter in the second plurality of filters is fired, thesubject is provided with a warning corresponding to the respectivefilter. In some embodiments, the second plurality of filters includesone or more of a first liver disease filter and a first drug interactionfilter. However, unlike filters in the first plurality of filters,filters in the second plurality of filters do not automaticallyterminate the process without delivery of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject.

The method continues by obtaining acknowledgment from the subject forthe warning issued to the subject by any filter in the second pluralityof filters. In some embodiments, acknowledgment from the subject is awritten acknowledgement, a verbal acknowledgment, or an electronicacknowledgment such as an electronic signature.

The method continues by proceeding with a fulfillment process when nofilter in the first plurality of filters has been fired and the subjecthas acknowledged each warning associated with each filter in the secondplurality of filters that was fired.

In some embodiments, the fulfillment process includes storing anindication in a subject profile of an initial order for thedihydropyridine-type calcium channel blocker pharmaceutical composition,communicating an over-the-counter drug label for thedihydropyridine-type calcium channel blocker pharmaceutical composition,and authorizing, upon confirmation from the subject that theover-the-counter drug label has been received and read, provision of thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition has the structure:

where,

-   -   Y is —(CH₂)₂—, —(CH₂)₃—, —CH₂CH(CH₃)—, or —CH₂C(CH₃)₂—;    -   R is aryl;    -   R¹ and R² are each independently C₁-C₄ alkyl or 2-methoxyethyl;    -   R³ is hydrogen, C₁-C₄ alkyl, 2—(C₁-C₄ alkoxy)ethyl,        cyclopropylmethyl, benzyl, or —(CH₂)_(m)COR₄ where m is 1, 2 or        3, and    -   R⁴ is hydroxy, C₁-C₄ alkoxy or —NR⁵R⁶ where R⁵ and R⁶ are each        independently hydrogen or C₁-C₄ alkyl.    -   In such embodiments, aryl is phenyl, the phenyl substituted by        one or two of nitro, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy,        trifluoromethyl or cyano, 1-naphthyl, or 2-naphthyl.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition includes amlodipine or a pharmaceuticallyacceptable salt thereof (e.g., mesylate, maleate, etc.) In someembodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition includes amlodipine besylate. In someembodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition includes isradipine, nifedipine, ornisoldipine.

In one aspect, the present disclosure provides a method for qualifying asubject (e.g., a subject who was previously qualified to receive aprovision of the dihydropyridine-type calcium channel blockerpharmaceutical composition) for a re-order of the dihydropyridine-typecalcium channel blocker pharmaceutical composition (e.g., which isoptionally performed in conjunction with a method for qualifying thesubject for a first order of the dihydropyridine-type calcium channelblocker pharmaceutical composition). The method includes are-fulfillment procedure. The re-fulfillment procedure includesconducting a second survey of the subject in order to obtain a secondplurality of survey results. In some embodiments, the second surveyresults includes one or more of: whether the subject is one of pregnant,breastfeeding, or planning to become pregnant, whether the subject hasexperienced an atherosclerotic cardiovascular event or had a heartprocedure since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition,whether the subject has started taking a medication that interacts withthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition,and whether the subject has developed a liver problem since receivingtheir last provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition.

The method also includes running all or a portion of the secondplurality of survey results against a third plurality of filters of thefirst category class. When a respective filter in the third plurality offilters is fired, the subject is deemed not qualified for thedihydropyridine-type calcium channel blocker pharmaceutical composition.Accordingly, the re-fulfillment process is terminated without deliveryof the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition to the subject. In some embodiments, the third plurality offilters comprises a second pregnancy filter that is fired at least whenthe second plurality of survey results indicates that the subject ispregnant or the subject is breastfeeding.

The method also includes running all or a portion of the secondplurality of survey results against a fourth plurality of filters of thesecond category class. When a respective filter in the fourth pluralityof filters is fired the subject is provided with a warning correspondingto the respective filter. In some embodiments, the fourth plurality offilters includes one or more of an atherosclerotic cardiovascular eventfilter, a second drug interaction filter, and a second liver diseasefilter.

The method continues by obtaining acknowledgment from the subject forthe warning issued to the subject by any filter in the fourth pluralityof filters. When the re-fulfillment process is not already terminated bythe firing of a filter in the third plurality of filters and the subjecthas acknowledged each warning associated with each filter in the fourthplurality of filters that was fired, the method continues with are-fulfillment procedure.

In some embodiments, the re-fulfillment procedure includes storing anindication in the subject profile of a re-order for thedihydropyridine-type calcium channel blocker pharmaceutical composition,communicating an over-the-counter drug facts label for thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject, and authorizing, upon confirmation from the subject thatthe over-the-counter drug facts label has been received and read, are-order provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject.

In some embodiments, e.g., when the subject profile for the subject doesnot include a recent blood pressure for the subject, the method includesobtaining a blood pressure status of the subject, e.g., in the secondsurvey, and running the blood pressure status against a second bloodpressure filter, e.g., in the third plurality of filters of the firstcategory class.

In some embodiments, the second survey results further include whetherthe subject has developed a side effect associated with thedihydropyridine-type calcium channel blocker pharmaceutical compositionsince receiving their last provision of the dihydropyridine-type calciumchannel blocker pharmaceutical composition, and the method includesrunning the result against a side effect filter, e.g., in the fourthplurality of filters of the second category class.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an exemplary system topology that includes adihydropyridine-type calcium channel blocker pharmaceutical compositionover-the-counter (OTC) dispensing device for qualifying a human subjectfor over-the-counter delivery of a dihydropyridine-type calcium channelblocker pharmaceutical composition to lower blood pressure, a datacollection device for collecting subject data, one or more user devicesassociated with human subjects, and one or more dispensary destinationsfor distributing the dihydropyridine-type calcium channel blockerpharmaceutical composition over-the-counter, where the above-identifiedcomponents are interconnected, optionally through a communicationsnetwork, in accordance with an embodiment of the present disclosure.

FIG. 2 illustrates an example device for qualifying a human subject fordelivery of a dihydropyridine-type calcium channel blockerpharmaceutical composition over-the-counter to lower cholesterol inaccordance with various embodiments of the present disclosure.

FIG. 3 illustrates an example device associated with a human subject forqualifying the human subject for over-the-counter delivery of agliflozin Sodium-Glucose Cotransport 2 inhibitor pharmaceuticalcomposition for lowering blood sugar, e.g., thereby treating Type 2diabetes and/or maintaining sub-diabetic blood sugar levels, inaccordance with an embodiment of the present disclosure, where it willbe appreciated that the example device of FIG. 3 works in conjunctionwith the device of FIG. 2 to perform the methods illustrated in FIGS. 4through 8 in some embodiments by, for instance providing the device ofFIG. 2 with survey results and/or the results of firing filters of thepresent disclosure against such survey results but that, in alternativeembodiments, the device of FIG. 2 performs all the methods of thepresent disclosure and the device of FIG. 3 is not used. In stillfurther alternative embodiments, the device of FIG. 3 performs themethods of the present disclosure and the device of FIG. 2 is not used.

FIGS. 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H, and 4I collectively provide a flowchart of processes for qualifying a human subject for over-the-counterdelivery of a dihydropyridine-type calcium channel blockerpharmaceutical composition to lower blood pressure, where elements indashed boxes are optional, in accordance with various embodiments of thepresent disclosure.

FIGS. 5A, 5B, 5C, 5D, and 5E collectively illustrate a first survey of asubject for obtaining a first plurality of survey results in accordancewith an embodiment of the present disclosure.

FIG. 6 illustrates feedback from a first survey in accordance with anembodiment of the present disclosure.

FIGS. 7A, 7B, and 7C collectively illustrate an example method forqualifying a subject for an over-the-counter provision of adihydropyridine-type calcium channel blocker pharmaceutical composition,in accordance with an embodiment of the present disclosure.

FIGS. 8A and 8B collectively illustrate an example method for qualifyinga subject for a refill of an over-the-counter provisiondihydropyridine-type calcium channel blocker pharmaceutical compositionin accordance with an embodiment of the present disclosure.

In the figures, reference numbers refer to the same or equivalent partsof the present invention throughout the several figures of the drawing.

DETAILED DESCRIPTION

Hypertension is a growing health problem, in the United States andworldwide. Although hypertension can be effectively treated and/orprevented using established pharmaceutical compositions, access to thesedrugs is hindered by to the requirement for a prescription, as manyindividuals do not have adequate access and/or avoid the healthcaresystem for a variety of reasons. Accordingly, many people are notmanaging their hypertension or conditions related to hypertensionappropriately. While over-the-counter alternatives to these prescriptionpharmaceuticals would increase access to these compositions, therebyimproving population management of hypertension and conditions relatedto hypertension around the world, patients often have difficultyself-selecting themselves for an appropriate over-the-countermedication. Because inappropriate use of these drugs can result inineffective treatment and/or serious side-effects, better methods forselecting for, and treating patients with, other-the-counterhypertension medications are needed. The present disclosure provides,among other aspects, methods, systems, and computer readable media thatsolve these problems.

Reference will now be made in detail to implementations, examples ofwhich are illustrated in the accompanying drawings. In the followingdetailed description of implementations, numerous specific details areset forth in order to provide a thorough understanding of the presentinvention. However, it will be apparent to one of ordinary skill in theart that the present invention may be practiced without these specificdetails.

It will also be understood that, although the terms first, second, etc.may be used herein to describe various elements, these elements shouldnot be limited by these terms. These terms are only used to distinguishone element from another. For example, a first filter could be termed asecond filter, and, similarly, a second filter could be termed a firstfilter, without departing from the scope of the present disclosure. Thefirst filter and the second filter are both filters, but they are notthe same filter.

The terminology used in the present disclosure is for the purpose ofdescribing particular embodiments only and is not intended to belimiting of the invention. As used in the description of the inventionand the appended claims, the singular forms “a,” “an,” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will also be understood that the term “and/or”as used herein refers to and encompasses any and all possiblecombinations of one or more of the associated listed items. It will befurther understood that the terms “comprises” and/or “comprising,” whenused in this specification, specify the presence of stated features,integers, steps, operations, elements, and/or components, but do notpreclude the presence or addition of one or more other features,integers, steps, operations, elements, components, and/or groupsthereof.

As used herein, the term “if” may be construed to mean “when” or “upon”or “in response to determining” or “in response to detecting,” dependingon the context. Similarly, the phrase “if it is determined” or “if [astated condition or event] is detected” may be construed to mean “upondetermining” or “in response to determining” or “upon detecting [thestated condition or event]” or “in response to detecting [the statedcondition or event],” depending on the context.

As used herein, the term “over-the-counter” means to provide by retailpurchase, subject to the constraints disclosed herein, but without aprescription or license from a physician or medical practitioner.

As used herein, the term “pharmaceutical compound” refers to anyphysical state of a material. Pharmaceutical compounds include but arenot limited to capsules, tablets, liquids, topical formulations, andinhaled formulations.

As used herein, the term “contraindication” refers to a condition thatmakes a treatment, e.g., over-the-counter use of a dihydropyridine-typecalcium channel blocker pharmaceutical composition, inadvisable.Contraindications include physical characteristics of a subject, e.g.,pregnancy or liver disease, and contemporaneous drug use, e.g.,dihydropyridine-type calcium channel blocker pharmaceutical compositionuse. In the present context, identification of a contraindication firesa filter of a first category class, which prevents authorizing provisionof a dihydropyridine-type calcium channel blocker pharmaceuticalcomposition, in accordance with some implementations of the methods,systems, and software disclosed herein.

As used herein, the term “risk factor” refers to a condition that makesa treatment, e.g., over-the-counter use of a dihydropyridine-typecalcium channel blocker pharmaceutical composition, possiblyinadvisable. Risk factors include physical characteristics of a subject,e.g., a blood pressure reading, and contemporaneous drug use, e.g., useof a blood pressure medication. In the present context, identificationof a risk factor fires a filter of a second category class, whichprevents authorizing provision of a dihydropyridine-type calcium channelblocker pharmaceutical composition without confirmation that the subjecthas discussed the risk factor with a medical professional, in accordancewith some implementations of the methods, systems, and softwaredisclosed herein.

As used herein, “drug interactions,” e.g., with a dihydropyridine-typecalcium channel blocker, include pharmacokinetic drug interactions andpharmacodynamics drug interactions. Generally, a pharmacokinetic druginteraction is an interaction between two drugs (e.g., adihydropyridine-type calcium channel blocker and a second drug) thatresult in alterations in the absorption, transport, distribution,metabolism, and/or excretion of either drug. Generally, apharmacokinetic drug interaction is an interaction between two drugs(e.g., a dihydropyridine-type calcium channel blocker and a second drug)that result in a direct change in the effect or either drug. For a morecomprehensive summary of pharmacokinetic drug interactions andpharmacodynamics drug interactions, see, Cascorbi, I, Dtsch ArzteblInt., 109(33-34):546-55 (2012), the content of which is herebyincorporated by reference.

In the context of the present disclosure, classification of a conditionas either a contraindication or a risk factor is specific to aparticular identity and dose of a dihydropyridine-type calcium channelblocker pharmaceutical composition being authorized for over-the-counteruse. Classification of a particular condition, e.g., contemporaneousdihydropyridine-type calcium channel blocker pharmaceutical compositionuse, may vary between different dihydropyridine-type calcium channelblocker pharmaceutical compositions (e.g., it may be classified as acontraindication for a first dihydropyridine-type calcium channelblocker, a risk factor for a second dihydropyridine-type calcium channelblocker, and/or neither for a third dihydropyridine-type calcium channelblocker). Likewise, a particular condition may be classified as acontraindication for use of a particular dihydropyridine-type calciumchannel blocker at a first over-the-counter dosage, classified as a riskfactor for the same particular dihydropyridine-type calcium channelblocker at a second (e.g., lower) over-the-counter dosage, and/orclassified as neither for the same particular dihydropyridine-typecalcium channel blocker at a third (e.g., lowest) over-the-counterdosage.

As used herein, whether a subject “has developed” a condition sincereceiving their last provision of a dihydropyridine-type calcium channelblocker refers to both conditions that are new to the subject, i.e., acondition that the subject did not have at the time they received theirlast provision of the dihydropyridine-type calcium channel blocker, andconditions that have been newly diagnosed, regardless of whether thecondition existed when the subject received their last provision of thedihydropyridine-type calcium channel blocker, i.e., a condition that thesubject was not aware of when they received their last provision of thedihydropyridine-type calcium channel blocker.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di-, tri- andmultivalent radicals, having the number of carbon atoms designated (e.g.C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbonradicals include, but are not limited to, groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “alkyl,” unlessotherwise noted, is also meant to optionally include those derivativesof alkyl defined in more detail below, such as “heteroalkyl.” Alkylgroups that are limited to hydrocarbon groups are termed “homoalkyl”.Exemplary alkyl groups include the monounsaturated C₉₋₁₀, oleoyl chainor the diunsaturated C₉₋₁₀, 12-13 linoeyl chain.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Furtherexemplary cycloalkyl groups include steroids, e.g., cholesterol and itsderivatives. Examples of heterocycloalkyl include, but are not limitedto, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 to 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl substituent groups (orrings) that contain from one to four heteroatoms selected from N, O, S,Si and B, wherein the nitrogen and sulfur atoms are optionally oxidized,and the nitrogen atom(s) are optionally quaternized. An exemplaryheteroaryl group is a six-membered azine, e.g., pyridinyl, diazinyl andtriazinyl. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes aryl, heteroaryl andheteroarene rings as defined above. Thus, the term “arylalkyl” is meantto include those radicals in which an aryl group is attached to an alkylgroup (e.g., benzyl, phenethyl, pyridylmethyl and the like) includingthose alkyl groups in which a carbon atom (e.g., a methylene group) hasbeen replaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl, and“heteroaryl”) are meant to optionally include both substituted andunsubstituted forms of the indicated species. Exemplary substituents forthese species are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: H, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, NRC(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, NRSO₂R′, —CN and —NO₂ ina number ranging from zero to (2 m′+1), where m′ is the total number ofcarbon atoms in such radical. R′, R″, R′″ and R″″ each preferablyindependently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, e.g., aryl substitutedwith 1-3 halogens, substituted or unsubstituted alkyl, alkoxy orthioalkoxy groups, or arylalkyl groups. When a compound of the inventionincludes more than one R group, for example, each of the R groups isindependently selected as are each R′, R″, R′″ and R″″ groups when morethan one of these groups is present. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include,but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “alkyl” is meant to include groups including carbon atoms boundto groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike). These terms encompass groups considered exemplary “alkyl groupsubstituents,” which are components of exemplary “substituted alkyl” and“substituted heteroalkyl” moieties.

Similar to the substituents described for the alkyl radical,substituents for the aryl heteroaryl and heteroarene groups aregenerically referred to as “aryl group substituents.” The substituentsare selected from, for example: groups attached to the heteroaryl orheteroarene nucleus through carbon or a heteroatom (e.g., P, N, O, S,Si, or B) including, without limitation, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycloalkyl, —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, NR′ C(O)NR″R′″, —NR″C(O)₂R′,NR—C(NR′R″R′″)═NR″″, NR C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,NRSO₂R′, —CN and —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, andfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number ofopen valences on the aromatic ring system. Each of the above-namedgroups is attached to the heteroarene or heteroaryl nucleus directly orthrough a heteroatom (e.g., P, N, O, S, Si, or B); and where R′, R″, R′″and R″″ are preferably independently selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl. When a compound of the invention includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′ and R″″ groups when more than one of these groups ispresent.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N),sulfur (S) and silicon (Si), boron (B) and phosphorous (P).

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycloalkyl groups.

The term “salt(s)” includes salts of the compounds prepared by theneutralization of acids or bases, depending on the particular ligands orsubstituents found on the compounds described herein. When compounds ofthe present invention contain relatively acidic functionalities, baseaddition salts can be obtained by contacting the neutral form of suchcompounds with a sufficient amount of the desired base, either neat orin a suitable inert solvent. Examples of base addition salts includesodium, potassium calcium, ammonium, organic amino, or magnesium salt,or a similar salt. Examples of acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids, and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,butyric, maleic, malic, malonic, benzoic, succinic, suberic, fumaric,lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts. Hydrates of the salts are also included.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure or be stereoisomeric mixtures. Inaddition, it is understood that, in any compound described herein havingone or more double bond(s) generating geometrical isomers that can bedefined as E or Z, each double bond may independently be E or Z amixture thereof. Likewise, it is understood that, in any compounddescribed, all tautomeric forms are also intended to be included.

In one aspect of the present disclosure survey of a subject is conductedto obtain survey results in order to determine if the subject qualifiesfor an over-the-counter (OTC) dihydropyridine-type calcium channel(e.g., L-type calcium channel, DHP channel) blocker pharmaceuticalcomposition for lowering blood pressure, e.g., thereby, treating orpreventing an atherosclerotic cardiovascular disease. The survey resultsare used as the basis for running filters of a first category class. Ifthe triggering conditions of any of the filters in the first categoryclass are fired, the subject does not qualify for the OTCdihydropyridine-type calcium channel blocker pharmaceutical composition.The survey results are also used as the basis for running filters of asecond category class. If the triggering conditions of any of thefilters in the second category class are fired, the subject is providedwith warning messages associated with the respective filters of thesecond category class that have been fired. If none of the filters inthe first category class are fired and the subject successfullyaddresses the warning messages associated with the respective filters ofthe second category class that have been fired a fulfillment process isinitiated for OTC delivery of the dihydropyridine-type calcium channelblocker pharmaceutical composition.

FIG. 1 illustrates an example of an integrated system 48 for conductingone or more surveys of subjects in order to qualifying the subjects forOTC delivery of a dihydropyridine-type calcium channel blockerpharmaceutical composition. The integrated system 48 includes one ormore connected user devices 102. The user devices 102 are configured forentering survey data and making requests for the dihydropyridine-typecalcium channel blocker pharmaceutical composition. The system 48 alsoincludes one or more dispensary destination devices 104 that areconfigured to receive instructions in order to provide thedihydropyridine-type calcium channel blocker pharmaceutical compositionto qualifying subjects. Furthermore, the system 48 includes adihydropyridine-type calcium channel blocker pharmaceutical compositionover-the-counter (OTC) dispensing device 250 and one or more datacollection devices 200 that are configured for collecting subject data.

Throughout the present disclosure, the data collection device 200 andthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition OTC dispensing device 250 will be referenced as separatedevices solely for purposes of clarity. That is, the disclosedfunctionality of the data collection device 200 and the disclosedfunctionality of the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 are contained inseparate devices as illustrated in FIG. 1 . However, it will beappreciated that, in fact, in some embodiments, the disclosedfunctionality of the data collection device 200 and the disclosedfunctionality of the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 are contained in asingle device.

With the integrated system 48, survey results from the subjects are runagainst a first plurality of filters (e.g., filter 216-1, filter 216-2,filter 216-4, etc.) When a filter in the first plurality of filters(e.g., filter 216) is fired for a respective subject, the respectivesubject is deemed not qualified for the dihydropyridine-type calciumchannel blocker pharmaceutical composition. The survey results are alsorun against a second plurality of filters (e.g., filter 222-1, filter222-2, filter 222-6, etc.) When a respective filter in the secondplurality is fired for a respective subject, the respective subject isprovided with a warning (e.g., filter warning 226) associated with therespective filter. In some embodiments the survey results are runagainst the first plurality of filters and the second plurality offilters concurrently. In some embodiments the survey results are runagainst the first plurality of filters and then against the secondplurality of filters. The method enabled by the integrated system 48proceeds to a fulfillment process when no filter in the first pluralityfires and the subject has acknowledged, or otherwise successfullyaddressed, each warning associated with each filter in the secondplurality of filters that fired. As part of the fulfillment process, thecomposition order is stored (e.g., in a user profile 234 associated withthe subject to receive the drug), a drug facts label (e.g., drug factslabel 230) for the dihydropyridine-type calcium channel blocker iscommunicated to the qualifying subject. Upon subject confirmation thatthe label has been read, authorization is granted to dispense thedihydropyridine-type calcium channel blocker.

Referring to FIG. 1 , the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 qualifies a subjectfor over-the-counter delivery of a dihydropyridine-type calcium channelblocker pharmaceutical composition to lower blood pressure. Toaccomplish this, the data collection device 200, which is in electricalcommunication with the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250, receives surveyresults originating from one or more user devices 102 associated withcorresponding subjects. In some embodiments, the data collection device200 receives such survey results directly from the user devices 102. Forinstance, in some embodiments the data collection device 200 receivesthis data wirelessly through radio-frequency signals. In someembodiments, such signals are in accordance with an 802.11 (Wi-Fi),Bluetooth, or ZigBee standard. In some embodiments, the data collectiondevice 200 receives such data directly, analyzes the data, and passesthe analyzed data to the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250.

In some embodiments, the data collection device 200 and/or thedihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250 is not proximate to the subject and/or doesnot have wireless capabilities or such wireless capabilities are notused for the purpose of acquiring survey results. In such embodiments, acommunication network 106 may be used to survey questions (e.g., surveyquestions 208, 212) from the dihydropyridine-type calcium channelblocker pharmaceutical composition OTC dispensing device 250 to userdevices 102 and the answers to such survey questions from the userdevices 102 to the data collection device 200 and/or thedihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250. Further, in some embodiments thecommunication network 106 is used to communicate authorization todispense the dihydropyridine-type calcium channel blocker surveyquestions from the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 to dispensarydestination devices 104.

Examples of networks 106 include, but are not limited to, the World WideWeb (WWW), an intranet and/or a wireless network, such as a cellulartelephone network, a wireless local area network (LAN) and/or ametropolitan area network (MAN), and other devices by wirelesscommunication. The wireless communication optionally uses any of aplurality of communications standards, protocols and technologies,including but not limited to Global System for Mobile Communications(GSM), Enhanced Data GSM Environment (EDGE), high-speed downlink packetaccess (HSDPA), high-speed uplink packet access (HSUPA), Evolution,Data-Only (EV-DO), HSPA, HSPA+, Dual-Cell HSPA (DC-HSPDA), long termevolution (LTE), near field communication (NFC), wideband code divisionmultiple access (W-CDMA), code division multiple access (CDMA), timedivision multiple access (TDMA), Bluetooth, Wireless Fidelity (Wi-Fi)(e.g., IEEE 802.11a, IEEE 802.11ac, IEEE 802.11ax, IEEE 802.11b, IEEE802.11g and/or IEEE 802.11n), voice over Internet Protocol (VoIP),Wi-MAX, a protocol for e-mail (e.g., Internet message access protocol(IMAP) and/or post office protocol (POP)), instant messaging (e.g.,extensible messaging and presence protocol (XMPP), Session InitiationProtocol for Instant Messaging and Presence Leveraging Extensions(SIMPLE), Instant Messaging and Presence Service (IMPS)), and/or ShortMessage Service (SMS), or any other suitable communication protocol,including communication protocols not yet developed as of the filingdate of the present disclosure.

Of course, other topologies of the system 48 are possible. For instance,rather than relying on a communications network 106, the one or moreuser devices 102 and the one or more dispensary destination devices 104may communicate directly to the data collection device 200 and/or thedihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250. Further, the data collection device 200and/or the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition OTC dispensing device 250 may constitute a portableelectronic device, a server computer, or in fact constitute severalcomputers that are linked together in a network, be a virtual machine ina cloud computing context, be a container in a cloud computer context,or a combination thereof. As such, the exemplary topology shown in FIG.1 merely serves to describe the features of an embodiment of the presentdisclosure in a manner that will be readily understood to one of skillin the art.

Turning to FIG. 2 with the foregoing in mind, an exemplarydihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250 configured for determining whether a subjectis qualified for OTC delivery of a dihydropyridine-type calcium channelblocker is depicted. Referring to FIG. 2 , in typical embodiments, thedihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250 comprises one or more computers. For purposesof illustration in FIG. 2 , the dihydropyridine-type calcium channelblocker pharmaceutical composition OTC dispensing device 250 isrepresented as a single computer that includes all of the functionalityfor qualifying a human subject for over-the-counter delivery of adihydropyridine-type calcium channel blocker pharmaceutical compositionto lower blood pressure. However, the present disclosure is not limitedthereto. In some embodiments, the functionality for qualifying a humansubject for over-the-counter delivery of a dihydropyridine-type calciumchannel blocker pharmaceutical composition to lower blood pressure isspread across any number of networked computers and/or resides on eachof several networked computers, is hosted on one or more virtualmachines at a remote location accessible across the communicationsnetwork 106, and/or is hosted on one or more containers at a remotelocation accessible across the communications network 106. One of skillin the art will appreciate that any of a wide array of differentcomputer topologies are used for the application and all such topologiesare within the scope of the present disclosure.

The dihydropyridine-type calcium channel blocker pharmaceuticalcomposition OTC dispensing device 250 of FIG. 2 is configured to conducta first survey (e.g., using assessment module 252 to perform an initialqualification of the subject for provision of a dihydropyridine-typecalcium channel blocker pharmaceutical composition) and/or a secondsurvey (e.g., using reassessment module 254 to perform are-qualification of the subject for provision of a dihydropyridine-typecalcium channel blocker pharmaceutical composition). The first survey(e.g., the assessment) comprises a variety of questions 208, 212associated with filters 216, 222 within a plurality of filters of thefirst filter category class 214 and a plurality of filters in the secondfilter category class 220, respectively. Answers to the questions in thefirst survey received by the device are run against filters of a firstcategory class 216-1 and filters of a second category class 220-1 withinthe first and second pluralities of filters 214-1, 216-1, respectively.Similarly, the second survey (e.g., the reassessment) also comprises avariety of questions associated with filters 216, 222 within a pluralityof filters of a first category class 214-2 and a plurality of filters ofa second category class 220-2, respectively. Answers to the questions inthe second survey received by the device are run against filters of afirst category class 216-2 and filters of a second category class 220-2,e.g., within the first and second pluralities of filters, respectively.Filters 216 of the first filter category class 214 are configured toterminate the qualification process when fired. Filters 222 of thesecond filter category class 220 are configured to provide the subjectwith a warning associated with a corresponding survey question. In otherwords, the device of FIG. 2 is configured to accumulate results from asurvey (e.g., survey questions 208 and survey questions 212) and run theresults against corresponding filters (e.g., filters 216 and filters222, respectively) in order to determine if a subject is qualified forOTC delivery of a dihydropyridine-type calcium channel blockerpharmaceutical composition.

In the present disclosure, a plurality of filters refers to a series, orset, or filters in either the first filter category class or the secondcategory class. For instance, in some embodiments, a plurality offilters of the first filter category class 214 can comprise any subsetof filters 216 of the first filter category class. As an example, insome embodiments a plurality of filters of the first category classcomprises filters 216-1, 216-2, 216-3, . . . , 216-i, or any combinationthereof. Similarly, a plurality of filters of the second filter categoryclass 220 can comprise any set of filters 222 of the second filtercategory class. Moreover, in some embodiments a plurality of filters ofthe second category class comprises filters 222-1, 222-2, 222-3, . . . ,222-i, or any combination thereof.

Continuing to refer to FIG. 2 , in some embodiments, the dispensingdevice 250 comprises one or more processing units (CPU's) 274, a networkor other communications interface 284, a memory 192 (e.g., random accessmemory), one or more magnetic disk storage and/or persistent devices 290optionally accessed by one or more controllers 288, one or morecommunication busses 213 for interconnecting the aforementionedcomponents, a user interface 278, the user interface 278 including adisplay 282 and input 280 (e.g., keyboard, keypad, touch screen), and apower supply 276 for powering the aforementioned components. In someembodiments, data in memory 192 is seamlessly shared with non-volatilememory 290 using known computing techniques such as caching. In someembodiments, memory 192 and/or memory 290 includes mass storage that isremotely located with respect to the central processing unit(s) 274. Inother words, some data stored in memory 192 and/or memory 290 may infact be hosted on computers that are external to thedihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250 but that can be electronically accessed by thedihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250 over an Internet, intranet, or other form ofnetwork or electronic cable (illustrated as element 106 in FIG. 2 )using network interface 284.

In some embodiments, the memory 192 of the dihydropyridine-type calciumchannel blocker pharmaceutical composition OTC dispensing device 250stores one or more of:

-   -   an operating system 202 that includes procedures for handling        various basic system services;    -   an assessment module 252 for qualifying a subject for an initial        over-the-counter delivery of a dihydropyridine-type calcium        channel blocker pharmaceutical composition to lower blood        pressure, e.g., treating or preventing heart disease, by        communicating survey questions, obtaining results therefrom, and        applying the results to qualifying filters, the assessment        module including:        -   a first filter category class 214-1, including filters 216            (e.g., a first plurality of filters), each respective filter            216 in the first filter category class 214-1 associated with            one or more survey questions 208 and one or more triggering            conditions 218;        -   a second filter category class 220-1, including filters 222            (e.g., a second plurality of filters), each respective            filter 222 in the second filter category class 220-1            associated with one or more survey questions 208, triggering            conditions 224, and warnings 226;    -   a fulfillment module 228-1 for executing a fulfillment process        when no filter 216 in the first filter category class 214-1 has        been fired for a subject and the subject has acknowledged each        warning 226 associated with each filter 222 in the second filter        category class 220-1 that was fired as a result of answers by        the subject to the survey questions 208, where the fulfillment        process includes communicating an over-the-counter drug facts        label 230 for the dihydropyridine-type calcium channel blocker        pharmaceutical composition to the subject and receiving        confirmation from the subject that the over-the-counter drug        facts label has been received and read;    -   a reassessment module 254 for qualifying a subject for a        subsequent over-the-counter delivery of a dihydropyridine-type        calcium channel blocker pharmaceutical composition to lower        blood pressure, e.g., treating or preventing heart disease, by        communicating survey questions, obtaining results therefrom, and        applying the results to qualifying filters, the assessment        module including:        -   a first filter category class 214-2, including filters 216            (e.g., a third plurality of filters), each respective filter            216 in the first filter category class 214-2 associated with            one or more survey questions 208 and one or more triggering            conditions 218;        -   a second filter category class 220-2, including filters 222            (e.g., a second plurality of filters), each respective            filter 222 in the second filter category class 220-2            associated with one or more survey questions 208, triggering            conditions 224, and warnings 226;    -   a re-fulfillment module 228-2 for executing a re-fulfillment        process when no filter 216 in the first filter category class        214-2 has been fired for a subject and the subject has        acknowledged each warning 226 associated with each filter 222-2        in the second filter category class 220 that was fired as a        result of answers by the subject to the survey questions 212,        where the re-fulfillment process includes communicating an        over-the-counter drug facts label 230 for the        dihydropyridine-type calcium channel blocker pharmaceutical        composition to the subject and receiving confirmation from the        subject that the over-the-counter drug facts label has been        received and read;    -   a subject profile data store 232 comprising a user profile 234        for each of a plurality of subjects, each respective user        profile 234 including information (e.g., shipping information,        billing information, biometric information, etc.) about a        corresponding subject in the plurality of subjects, an initial        order date and destination 236, and any re-order date and the        destination 238 for the dihydropyridine-type calcium channel        blocker pharmaceutical composition made by the corresponding        subject using the dihydropyridine-type calcium channel blocker        pharmaceutical composition OTC dispensing device 250;    -   an adverse event module 242 for identifying and aggregating        records of adverse events associated with a plurality of        subjects, e.g., corresponding to the firing of a filter 216 in        the first filter category class 214-2 during a re-fulfillment        process;    -   a reimbursement module 240 for determining eligibility and/or        communicating an insurance claim associated with delivery of the        dihydropyridine-type calcium channel blocker, e.g., based on        insurance information stored in a respective user profile 234.

In some embodiments, the assessment module 252, reassessment module 254,and/or fulfillment module 228 are accessible within any browser (e.g.,phone, tablet, laptop/desktop, or smartwatch). In some embodiments, theassessment module 252, reassessment module 254, and/or fulfillmentmodule 228 run on native device frameworks, and is available fordownload onto a user device 102 running an operating system 202 such asAndroid, iOS, or WINDOWS.

In some implementations, one or more of the above identified dataelements or modules (e.g., assessment module 252, fulfillment module228-1, etc.) of the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 for qualifying ahuman subject for over-the-counter delivery of a dihydropyridine-typecalcium channel blocker pharmaceutical composition to lower bloodpressure are stored in one or more of the previously described memorydevices, and correspond to a set of instructions for performing afunction described above. The above-identified data, modules or programs(e.g., sets of instructions) need not be implemented as separatesoftware programs, procedures or modules, and thus various subsets ofthese modules may be combined or otherwise re-arranged in variousimplementations. In some implementations, the memory 192 and/or 290optionally stores a subset of the modules and data structures identifiedabove. Furthermore, in some embodiments the memory 192 and/or 290 storesadditional modules and data structures not described above.

In some embodiments, a dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 for qualifying ahuman subject for over-the-counter delivery of a dihydropyridine-typecalcium channel blocker pharmaceutical composition to lower bloodpressure is a smart phone (e.g., an iPhone, Blackberry, etc.), a laptop,a tablet computer, a desktop computer, a smart watch, or another form ofelectronic device (e.g., a gaming console). In some embodiments, thedihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250 is not mobile. In some embodiments, thedihydropyridine-type calcium channel blocker pharmaceutical compositionOTC dispensing device 250 is mobile.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 is not a smartphone but rather is a tablet computer, desktop computer, emergencyvehicle computer, or other form or wired or wireless networked device.In the interest of brevity and clarity, only a few of the possiblecomponents of the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 are shown in FIG. 2in order to better emphasize the additional software modules that areinstalled on the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250.

FIG. 3 provides a description of a user device 102 that can be used withthe present disclosure. The user device 102 illustrated in FIG. 3 hasone or more processing units (CPU's) 374, peripherals interface 370,memory controller 368, a network or other communications interface 384,a memory 392 (e.g., random access memory), a user interface 378, theuser interface 378 including a display 382 and input 380 (e.g.,keyboard, keypad, touch screen), an optional accelerometer 317, anoptional GPS 319, optional audio circuitry 372, an optional speaker 360,an optional microphone 362, one or more optional intensity sensors 364for detecting intensity of contacts on the user device 102 (e.g., atouch-sensitive surface such as a touch-sensitive display system 382 ofthe user device 102), an optional input/output (I/O) subsystem 366, oneor more optional optical sensors 373, one or more communication busses313 for interconnecting the aforementioned components, and a powersupply 376 for powering the aforementioned components.

In some embodiments, the input 380 is a touch-sensitive display, such asa touch-sensitive surface. In some embodiments, the user interface 378includes one or more soft keyboard embodiments. The soft keyboardembodiments may include standard (e.g., QWERTY) and/or non-standardconfigurations of symbols on the displayed icons.

The user device 102 illustrated in FIG. 3 optionally includes, inaddition to accelerometer(s) 317, a magnetometer (not shown) and a GPS319 (or GLONASS or other global navigation system) receiver forobtaining information concerning the location and orientation (e.g.,portrait or landscape) of the user device 102 and/or for determining anamount of physical exertion by the subject.

It should be appreciated that the user device 102 illustrated in FIG. 3is only one example of a multifunction device that may be used forperforming a survey (e.g., first survey 206) in order to qualify forover-the-counter delivery of a dihydropyridine-type calcium channelblocker pharmaceutical composition to lower blood pressure, and that theuser device 102 optionally has more or fewer components than shown,optionally combines two or more components, or optionally has adifferent configuration or arrangement of the components. The variouscomponents shown in FIG. 3 are implemented in hardware, software,firmware, or a combination thereof, including one or more signalprocessing and/or application specific integrated circuits.

Memory 392 of the user device 102 illustrated in FIG. 3 optionallyincludes high-speed random access memory and optionally also includesnon-volatile memory, such as one or more magnetic disk storage devices,flash memory devices, or other non-volatile solid-state memory devices.Access to memory 392 by other components of the dihydropyridine-typecalcium channel blocker pharmaceutical composition OTC dispensing device250, such as CPU(s) 374 is, optionally, controlled by the memorycontroller 368. In some embodiments, the memory 392 of the user device102 illustrated in FIG. 3 optionally includes:

-   -   an operating system 302 that includes procedures for handling        various basic system services;    -   the assessment module 252 described above in conjunction with        the dihydropyridine-type calcium channel blocker pharmaceutical        composition OTC dispensing device 250;    -   the first category class 214 described above in conjunction with        the dihydropyridine-type calcium channel blocker pharmaceutical        composition OTC dispensing device 250 further comprising a        pregnancy filter 216-1, a dihydropyridine-type calcium channel        blocker filter 216-2, a first blood pressure filter 216-3, a        second blood pressure filter 216-4, an age filter 216-5, and a        pooled cohort equation filter 216-6; and    -   the second category class 220 described above in conjunction        with the dihydropyridine-type calcium channel blocker        pharmaceutical composition OTC dispensing device 250 comprising        a liver disease filter 222-1, a pooled cohort equation filter        222-2, an age filter 222-3, a drug interaction filter 222-4, an        alcohol consumption filter 222-5, an adverse reaction filter        222-6, and an atherosclerotic cardiovascular event filter 222-7;

In some embodiments, the optional accelerometer 317, optional GPS 319,and/or magnetometer (not shown) of the user device 102 or suchcomponents are used to recommend to qualifying subjects one or moresuitable destinations for delivery of the dihydropyridine-type calciumchannel blocker pharmaceutical composition over-the-counter. In someembodiments, the GPS 319 is used to determine if a subject isgeographically restricted for OTC delivery of the dihydropyridine-typecalcium channel blocker pharmaceutical composition. Geographicalrestrictions include but are not limited to a subject residing outsideof delivery or shipping regions, marketing restrictions, and/orgovernment regulations.

The peripherals interface 370 can be used to couple input and outputperipherals of the device to CPU(s) 374 and memory 392. The one or moreprocessors 374 run or execute various software programs and/or sets ofinstructions stored in memory 392, such as the survey module 204, toperform various functions for the user device 102 and to process data.

In some embodiments, the peripherals interface 370, CPU(s) 374, andmemory controller 368 are, optionally, implemented on a single chip. Insome other embodiments, they are implemented on separate chips.

RF (radio frequency) circuitry of network interface 384 receives andsends RF signals, also called electromagnetic signals. In someembodiments, the survey module 204, survey questions 208/212, answers tosurvey questions 208/212, and/or the over-the-counter drug facts label230 are communicated to the subject device 102 using this RF circuitry.In some embodiments, the RF circuitry 384 converts electrical signalsto/from electromagnetic signals and communicates with communicationsnetworks and other communications devices and/or the data collectiondevice 200 and/or the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device 250 via theelectromagnetic signals. The RF circuitry 384 optionally includeswell-known circuitry for performing these functions, including but notlimited to an antenna system, an RF transceiver, one or more amplifiers,a tuner, one or more oscillators, a digital signal processor, a CODECchipset, a subscriber identity module (SIM) card, memory, and so forth.RF circuitry 384 optionally communicates with the communication network106. In some embodiments, the circuitry 384 does not include RFcircuitry and, in fact, is connected to the network 106 through one ormore hard wires (e.g., an optical cable, a coaxial cable, or the like).

In some embodiments, the audio circuitry 372, the optional speaker 360,and the optional microphone 362 provide an audio interface between thesubject and the user device 102. The audio circuitry 372 receives audiodata from the peripherals interface 370, converts the audio data toelectrical signals, and transmits the electrical signals to the speaker360. The speaker 360 converts the electrical signals to human-audiblesound waves. In some embodiments, the speaker 260 converts theelectrical signals to human-inaudible sound waves. The audio circuitry372 also receives electrical signals converted by the microphone 362from sound waves. The audio circuitry 372 converts the electrical signalto audio data and transmits the audio data to peripherals interface 370for processing. Audio data is, optionally, retrieved from and/ortransmitted to the memory 392 and/or the RF circuitry 384 by theperipherals interface 370.

In some embodiments, the power supply 376 optionally includes a powermanagement system, one or more power sources (e.g., battery, alternatingcurrent (AC)), a recharging system, a power failure detection circuit, apower converter or inverter, a power status indicator (e.g., alight-emitting diode (LED)) and any other components associated with thegeneration, management and distribution of power in portable devices.

In some embodiments, the user device 102 optionally also includes one ormore optical sensors 373. The optical sensor(s) 373 optionally includecharge-coupled device (CCD) or complementary metal-oxide semiconductor(CMOS) phototransistors. The optical sensor(s) 373 receive light fromthe environment, projected through one or more lens, and converts thelight to data representing an image. The optical sensor(s) 373optionally capture still images and/or video. In some embodiments, anoptical sensor is located on the back of the user device 102, oppositethe display 382 on the front of the user device 102, so that the input380 is enabled for use as a viewfinder for still and/or video imageacquisition. In some embodiments, another optical sensor 373 is locatedon the front of the user device 102 so that the subject's image isobtained (e.g., to verify the health, condition, or identity of thesubject as part of qualifying the subject for over-the-counter deliveryof a dihydropyridine-type calcium channel blocker pharmaceuticalcomposition to lower blood pressure), to help diagnose a subject'scondition remotely, or to acquire visual physiological measurements ofthe subject, etc.)

As illustrated in FIG. 3 , the user device 102 preferably comprises anoperating system 302 that includes procedures for handling various basicsystem services. The operating system 302 (e.g., iOS, DARWIN, RTXC,LINUX, UNIX, OS X, WINDOWS, or an embedded operating system such asVxWorks) includes various software components and/or drivers forcontrolling and managing general system tasks (e.g., memory management,storage device control, power management, etc.) and facilitatescommunication between various hardware and software components.

In some embodiments the user device 102 is a smart phone or a smartwatch. In other embodiments, the user device 102 is not a smart phone ora smart watch but rather is a tablet computer, a desktop computer, anemergency vehicle computer, or other form or wired or wireless networkeddevice. In the interest of brevity and clarity, only a few of thepossible components of the user device 102 are shown in FIG. 3 in orderto better emphasize the additional software modules that are installedon the user device 102.

While the system 48 disclosed in FIG. 1 can work standalone, in someembodiments it can also be linked with electronic medical record systemsto exchange information in any way.

Now that details of a system 48 for qualifying a human subject forover-the-counter delivery of a dihydropyridine-type calcium channelblocker pharmaceutical composition to lower blood pressure have beendisclosed, details regarding a method (400), including processes andfeatures to be performed by the system, in accordance with an embodimentof the present disclosure, are disclosed with reference to FIGS. 4Athrough 4I. In some embodiments, such processes and features of thesystem are carried out by the assessment module 252, reassessment module254, fulfillment module 228-1, and/or re-fulfillment module 228-2illustrated in FIGS. 2 and 3 . In some embodiments, the assessmentmodule 252, reassessment module 254, fulfillment module 228-1, and/orre-fulfillment module 228-1 are a single software module. In the flowchart, elements in dashed boxes are considered to be optional.

Blocks 402-412. Referring to block 402 of FIG. 4A, a goal of the presentdisclosure is to qualify subjects for over-the-counter delivery of adihydropyridine-type calcium channel blocker pharmaceutical compositionto lower blood pressure, e.g., thereby, treating and/or preventing heartdisease, using a computer system such as a dihydropyridine-type calciumchannel blocker pharmaceutical composition OTC dispensing device 250. Asillustrated in FIG. 2 , the dihydropyridine-type calcium channel blockerpharmaceutical composition OTC dispensing device (e.g., device 250)comprises one or more processors (e.g., processor 274) and a memory(e.g., memory 192 and/or 290). The memory stores non-transitoryinstructions that, when executed by the one or more processors, performa method.

Referring to block 404, in some embodiments the dihydropyridine-typecalcium channel blocker pharmaceutical composition thedihydropyridine-type calcium channel blocker pharmaceutical compositionhas a structure of structure (I):

where:

-   -   Y is —(CH₂)₂—, —(CH₂)₃—, —CH₂CH(CH₃)—, or —CH₂C(CH₃)₂—;    -   R is aryl;    -   R¹ and R² are each independently C₁-C₄ alkyl or 2-methoxyethyl;    -   R³ is hydrogen, C₁-C₄ alkyl, 2—(C₁-C₄ alkoxy)ethyl,        cyclopropylmethyl, benzyl, or —(CH₂)_(m)COR⁴ where m is 1, 2 or        3 and R⁴ is hydroxy, C₁-C₄ alkoxy or —NR⁵R⁶ where R⁵ and R⁶ are        each independently hydrogen or C₁-C₄ alkyl.

In some embodiments, aryl is phenyl, the phenyl substituted by one ortwo of nitro, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, trifluoromethylor cyano, 1-naphthyl, or 2-naphthyl.

Referring to blocks 406-410, in some embodiments thedihydropyridine-type calcium channel blocker pharmaceutical compositionincludes amlodipine. In some embodiments, the dihydropyridine calciumchannel blocker includes a pharmaceutically acceptable salt ofamlodipine (e.g., mesylate, maleate). In some embodiments, thedihydropyridine-type calcium channel blocker pharmaceutical compositionincludes amlodipine besylate.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition includes one of isradipine (e.g., 3-methyl5-propan-2-yl4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate),nifedipine (e.g., 3,5-dimethyl2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate),nisoldipine (e.g., isobutyl methyl2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate).These dihydropyridine-type calcium channel blocker compositions aredescribed in McDonagh M S, et al., “Calcium Channel Blockers,” FinalReport, Portland (Oreg.): Oregon Health & Science University (2005), thecontent of which is hereby incorporated by reference.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition comprises any compound disclosed in U.S. Pat.No. 4,879,303, entitled “Pharmaceutically Acceptable Salts,” which ishereby incorporated by reference. In some embodiments, thedihydropyridine-type calcium channel blocker pharmaceutical compositioncomprises any compound disclosed in U.S. Pat. No. 4,572,909, entitled“2-(Secondary aminoalkoxymethyl) dihydropyridine derivatives asanti-ischaemic and antihypertensive agents,” which is herebyincorporated by reference.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition comprises any compound disclosed in U.S. Pat.No. 4,264,611, entitled “2,6-Dimethyl-4-2,3-disubstitutedphenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetricdiesters having hypotensive properties, as well as method for treatinghypertensive conditions and pharmaceutical preparations containingsame,” which is hereby incorporated by reference. In some embodiments,the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition comprises any compound disclosed in U.S. Pat. No. 4,803,081,entitled “New Pharmaceutical Preparations with Extended Release,” whichis hereby incorporated by reference.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition comprises any compound disclosed in U.S. Pat.No. 4,412,986, entitled “Nifedipine-containing Solid PreparationComposition,” which is hereby incorporated by reference. In someembodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition comprises any compound disclosed in U.S. Pat.No. 3,784,684, entitled “Coronary Dilator in a Pharmaceutical DosageUnit Form,” which is hereby incorporated by reference. In someembodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition comprises any compound disclosed in U.S. Pat.No. 3,644,627, entitled “Pharmaceutical compositions and methods forproducing coronary dilation with 4-aryl-1,4-dihydropyridinederivatives,” which is hereby incorporated by reference.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition comprises any compound disclosed in U.S. Pat.No. 4,466,972, entitled “Benzoxadiazoles and Benzothiadiazoles, TheirPreparation and Pharmaceutical Compositions Containing Them,” which ishereby incorporated by reference.

Contraindications described in the present disclosure arenon-exhaustive. The skilled artisan may know of other contraindicationsfor a particular the dihydropyridine-type calcium channel blockerpharmaceutical composition and/or treat risk factors ascontraindications dependent upon the intended use of thedihydropyridine-type calcium channel blocker pharmaceutical composition.In some embodiments, contraindications for use of aprescription-strength pharmaceutical agent are treated only as riskfactors, or not at all, when qualifying a subject for a lower-dose OTCuse of a dihydropyridine-type calcium channel blocker pharmaceuticalcomposition.

Referring to block 412, in some embodiments, the lowering of bloodpressure is to treat or prevent heart disease. Typically, this isaccomplished by a reduction in systemic vascular resistance and/orarterial pressure.

In some embodiments, a subject that has not received an over-the-counterprovision of the dihydropyridine-type calcium channel blocker willregister as a new user, and the device will create a corresponding userprofile (e.g., regardless of whether the subject previously received aprescription provision of the dihydropyridine-type calcium channelblocker. In some embodiments, the subject will register as a returningcustomer, e.g., if the subject has previously received anover-the-counter provision of the dihydropyridine-type calcium channelblocker and a corresponding user profile 234 already exists for theuser.

In some embodiments, the subject is prompted (702) to confirm that theyhave adequate privacy to provide sensitive medical information and/orthat they are in possession of medical information required to completethe qualification process. For example, in some embodiments the subjectis prompted (704) to confirm that they have knowledge of their bloodpressure, total cholesterol level, and HDL level.

Blocks 414-416 Referring to block 414 of FIG. 4A, the method includesconducting a first survey of the subject. By way of the first survey, afirst plurality of survey results to survey questions 208, 212 (e.g.,one or more of the survey questions set forth in Table 1) are obtained(e.g., the device transmits one or more survey questions to the user,prompting a response, and then receives a response to the one or moresurvey questions back from the subject). In some embodiments, the firstsurvey results include some or all of the characteristics listed inTable 1. For example, in some embodiments, the first plurality of surveyresults includes 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all16 of the characteristics listed in Table 1. In one embodiment, thefirst survey questions 208, 212 and results include at leastcharacteristics 1-15 as provided in Table 1.

It will be appreciated that the survey questions 208, 212 and filters216, 222 applied to the survey answers thereof may vary depending uponthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition being distributed. This is due to differences in thecontra-indication profiles of the various the dihydropyridine-typecalcium channel blocker pharmaceutical compositions, e.g., due todifferent drug-drug interactions, routes of drug clearance, etc. of thedifferent the dihydropyridine-type calcium channel blockerpharmaceutical compositions. For example, co-administration of 240milliliters (mL) of grapefruit juice with a single oral dose ofamlodipine 10 milligrams (mg) had no significant effect on thepharmacokinetics of amlodipine. However, co-administration of nifedipinewith grapefruit juice resulted in approximately a doubling in nifedipineblood the area under the curve of blood concentration versus time (AUC)and maximum serum concentration (C_(max)) with no change in half-life.As such, in some embodiments, a survey qualifying a subject for OTC useof nifedipine may ask whether the subject consumes grapefruit in theirdiet, while a survey qualifying a subject for OTC use of amlodipine maynot.

Referring to block 416, and as further illustrated in FIG. 7 , in someembodiments the first survey results include whether the subject is oneof pregnant, breastfeeding, or planning to become pregnant (e.g.,responsive to a survey question 502 such as the one illustrated in FIG.5A, e.g., that is associated with and/or applied to (705) a pregnancyfilter 216 of a first category class), whether the subject is taking adihydropyridine-type calcium channel blocker (e.g., responsive to asurvey question 208 that is associated with and/or applied to (710) adihydropyridine medication filter 216 of a first category class), asystolic blood pressure of the subject (e.g., responsive to a surveyquestion 208 that is associated with and/or applied to (715, 765) ablood pressure filter 216 of a first category class and/or a pooledcohort equation filter 216 of a first category class), a diastolic bloodpressure of the subject (e.g., responsive to a survey question 208 thatis associated with and/or applied to (715) a blood pressure filter 216of a first category class), whether the subject has ever had anatherosclerotic cardiovascular event (e.g., hospitalization for anginapectoris, coronary revascularization, myocardial infarction,cardiovascular death, resuscitated cardiac arrest, hospitalization forheart failure, stroke/TIA, or peripheral vascular disease) or had aheart procedure (e.g., responsive to a survey question 208 that isassociated with and/or applied to (765) a pooled cohort equation filter216 of a first category class), a gender of the subject (e.g.,responsive to a survey question 208 that is associated with and/orapplied to (765) a pooled cohort equation filter 216 of a first categoryclass), an age of the subject (e.g., responsive to a survey question 208that is associated with and/or applied to (730, 765) an age filter 216of a first filter class category and/or a pooled cohort equation filter216 of a first category class), a race of the subject (e.g., responsiveto a survey question 208 that is associated with and/or applied to (765)a pooled cohort equation filter 216 of a first category class), whetherthe subject is taking any blood pressure medications (e.g., responsiveto a survey question 208 that is associated with and/or applied to (765)a pooled cohort equation filter 216 of a first category class), adiabetes status of the subject (e.g., responsive to a survey question208 that is associated with and/or applied to (765) a pooled cohortequation filter 216 of a first category class), a smoking status of thesubject (e.g., responsive to a survey question 208 that is associatedwith and/or applied to (765) a pooled cohort equation filter 216 of afirst category class), a total cholesterol level of the subject (e.g.,responsive to a survey question 208 that is associated with and/orapplied to (765) a pooled cohort equation filter 216 of a first categoryclass), a high-density lipoprotein (HDL) cholesterol level of thesubject (e.g., responsive to a survey question 208 that is associatedwith and/or applied to (765) a pooled cohort equation filter 216 of afirst category class), whether the subject has ever had a liver problem(e.g., responsive to a survey question 208 that is associated withand/or applied to (770) a liver disease filter 222 of a second categoryclass), and whether the subject is taking one or more medications thatinteract with the dihydropyridine-type calcium channel blockerpharmaceutical composition, (e.g., responsive to a survey question 208that is associated with and/or applied to (775) a drug interactionfilter 222 of a second category class).

In some embodiments, the first survey includes questions that elicitresponses providing some or all of the characteristics listed inTable 1. In some embodiments, the survey includes questionscorresponding to each of the survey results required for the methodsdescribed herein. In other embodiments, the survey includes questionscorresponding to only a subset of the survey results required for themethods described herein. In such embodiments, other survey resultsrequired for the methods described herein are acquired through othermeans (e.g., upon registration/subscription for a service associatedwith qualifying the subject for over-the-counter medication, from ahealthcare provider, from a prior survey, from a database associatedwith a pharmacy, from an electronic health record associated with thesubject, from the subject profile data store 232, etc.) For example, insome embodiments, the subject provides a personal medical identificationassociated with an insurer, a hospital, or other healthcare provider andinformation about the subject required for the methods described herein,e.g., one or more survey results, is acquired from a preexistingdatabase associated with the personal medical identification (e.g., alast cholesterol or blood pressure measurement determined for thesubject).

TABLE 1 Exemplary First Survey Questions Result ExemplaryCharacteristics 1 whether the subject pregnant or breastfeeding 2whether the subject is already taking a dihydropyridine-type calciumchannel blocker 3 a systolic blood pressure of the subject 4 a diastolicblood pressure of the subject 5 whether the subject has ever had anatherosclerotic cardiovascular event or a had a heart procedure 6 agender of the subject 7 an age of the subject 8 a race of the subject 9whether the subject is taking any blood pressure medications 10 adiabetes status of the subject 11 a smoking status of the subject 12 atotal cholesterol of the subject 13 a HDL cholesterol level of thesubject 14 whether the subject has ever had a liver problem 15 whetherthe subject is taking a medication that interacts with thedihydropyridine-type calcium channel blocker pharmaceutical composition16 whether the subject is allergic to the dihydropyridine-type calciumchannel blocker pharmaceutical composition

It is contemplated that, in some embodiments, any one or more of thesurvey questions 208, 212 provided in Table 1 will not be included inthe first survey (e.g., will not be used for the assessment. Forexample, in some embodiments, a characteristic associated with aparticular survey questions will be informative when qualifying asubject for one particular dihydropyridine-type calcium channel blockerbut not for another dihydropyridine-type calcium channel blocker. Forinstance, a survey question is queried for amlodipine qualifying surveysbut not for isradipine qualifying surveys. The skilled artisan willrecognize that different dihydropyridine-type calcium channel blockerscarry different risk and drug interaction profiles. Accordingly, surveyinformation required for qualifying a subject for access to onedihydropyridine-type calcium channel blocker with a known adverse druginteraction may not be necessary for qualifying the same subject foraccess to a second dihydropyridine-type calcium channel blocker.

Accordingly, it is contemplated that the first survey questions 208include any subset of survey results provided in Table 1. For brevity,all possible combinations of the survey questions 208, 212 provided inTable 1 are not specifically delineated here. However, the skilledartisan will easily be able to envision any particular subset of thesurvey questions 208, 212 provided in Table 1. Likewise, the skilledartisan may know of other survey questions, not provided in Table 1,that may be combined with any subset of the survey questions provided inTable 1 to form the first survey questions used in the methods describedherein.

In some embodiments, the first and/or second survey is conducted bytransmitting a plurality of questions to the subject, e.g., some or allof the survey questions, and receiving answers to the plurality ofsurvey questions before applying any of the answers to respectivefilters. For example, with reference to the workflow in FIG. 7 , thedevice transmits questions relating to all of the filters of the firstcategory class, all of the filters of the second category class, or allof the filters in the workflow (e.g., as a virtual survey where all ofthe questions are displayed in a single user interface, or as a seriesof questions displayed in consecutive user interfaces). After receivinganswers to all of the survey questions, the device then applies theanswers to all of the filters (e.g., sequentially or concurrently) todetermine whether the subject is qualified to receive provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition.In alternative embodiments, the device transmits questions relating tojust those filters of the first category class for which it could notobtain answers to the questions from an electronic database associatedwith the subject, such as electronic health record of the subject, andjust those filters of the second category class it could not obtainanswers to the questions from an electronic database associated with thesubject (e.g., as a virtual survey where such unanswered questions aredisplayed in a single user interface, or as a series of questionsdisplayed in consecutive user interfaces). After receiving answers toall of the survey questions, the device then applies the answers to allof the filters (e.g., sequentially or concurrently) to determine whetherthe subject is qualified to receive provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition.

In some embodiments, the first and/or second survey is conducted in aserial fashion, e.g., by transmitting a first question or a first groupof survey questions (e.g., associated with a single filter) to thesubject, receiving an answer to the single survey question or smallgroup of survey questions, and applying the answer or answers to afilter, prior to transmitting a second question or second group ofquestions to the subject. For example, with reference to the workflow inFIG. 7 , in some embodiments the device transmits a first question tothe subject, relating to the pregnancy and/or breastfeeding status ofthe subject (e.g., question 502 ‘Are you or do you plan to becomepregnant? Are you breastfeeding or planning to breastfeed?’ in FIG. 5A).After receiving the answer to the survey question (e.g., ‘yes or no’),the device applies the answer to a first pregnancy filter (705). If thefirst pregnancy filter is fired (e.g., in response to a “yes” answer),the device terminates (795-1) the process, and optionally provides theuser with a message relating to why they are being denied a provision ofthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition (e.g., as illustrated in FIG. 5B, message 504, advising thesubject that taking the dihydropyridine-type calcium channel blockerpharmaceutical composition creates a risk for the fetus/baby), asuggestion for following-up with a medical professional (e.g., asillustrated in FIG. 7A, when the survey answers indicate that thesubject is in hypertensive crisis (715-5), the device terminates theprocess (795-6) and advises that the subject seek immediate medicalattention), and/or a suggestion to make a lifestyle change (e.g., asillustrated in FIG. 7A, when the survey answers indicate that thesubject has slightly elevated blood pressure (715-2), the deviceterminates the process (795-3) and advises that the subject improvetheir diet or exercise routine which is consistent with current bloodpressure treatment guidelines), to treat or manage their blood pressure.

In some embodiments, the first survey includes questions that elicitresponses providing some or all of the characteristics listed inTable 1. In some embodiments, the survey includes questionscorresponding to each of the survey results required for the methodsdescribed herein. In other embodiments, the survey includes questionscorresponding to only a subset of the survey results required for themethods described herein. In such embodiments, the other survey resultsrequired for the methods described herein are acquired through othermeans (e.g., upon registration/subscription for a service associatedwith qualifying the subject for over-the-counter medication, from ahealthcare provider, from a prior survey, from a database associatedwith a pharmacy, etc.) For example, in some embodiments, the subjectprovides a personal medical identification associated with an insurer, ahospital, or other healthcare provider and information about the subjectrequired for the methods described herein, e.g., one or more surveyresults, is acquired from a preexisting database associated with thepersonal medical identification (e.g., a last cholesterol or bloodpressure measurement determined for the subject). The same applies tothe second survey 210 and corresponding results applied to the firstsurvey 206.

Blocks 418-452. Referring to block 418 of FIG. 4B, all or a portion ofthe first survey results are run against a first plurality of filters ofa first category class 214. As previously described, the first pluralityof filters comprises a subset of filters 216 of the first filtercategory class 214. When a respective filter in the first plurality offilters is fired (e.g., when a survey result indicates that a triggeringcondition 218 has been met), the subject is deemed not qualified fordelivery of the dihydropyridine-type calcium channel blockerpharmaceutical composition and the method is terminated without deliveryof the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition.

In some embodiments, e.g., when the method is terminated withoutdelivery of the dihydropyridine-type calcium channel blockerpharmaceutical composition, the subject is prevented from attempting torequalify for the dihydropyridine-type calcium channel blockerpharmaceutical composition for a predetermined period of time. Thisprevents the subject from abusing the systems and methods of the presentdisclosure.

Referring to blocks 420-452, specific filters 216 in the first pluralityof filters and their exemplary triggering conditions 218 that cause thecorresponding filter to fire are detailed.

In some embodiments, the first plurality of filters of the firstcategory class 214 includes some or all of the filters 216 listed inTable 2. For example, in some embodiments, the first plurality offilters results includes 2, 3, 4, or all 5 of the filters listed inTable 2.

TABLE 2 Exemplary First Plurality of Filters of the First Category ClassFilter Exemplary Criteria 1a a pregnancy filter 2a a dihydropyridinemedication filter 3a a blood pressure filter 4a an age filter 5a apooled cohort equation filter

In one embodiment, the first plurality of filters includes at leastfilters 1 a-5 a as provided in Table 2. In another embodiment, the firstplurality of filters includes at least filters 1 a, 2 a, 3 a, and 4 a asprovided in Table 2. In another embodiment, the first plurality offilters includes at least filters Ta, 2 a, 3 a, and 5 a as provided inTable 2. In another embodiment, the first plurality of filters includesat least filters Ta, 2 a, 4 a, and 5 a as provided in Table 2. Inanother embodiment, the first plurality of filters includes at leastfilters Ta, 3 a, 4 a, and 5 a as provided in Table 2. In anotherembodiment, the first plurality of filters includes at least filters 2a, 3 a, 4 a, and 5 a as provided in Table 2. In another embodiment, thefirst plurality of filters includes at least filters 1 a, 2 a, and 3 aas provided in Table 2. In another embodiment, the first plurality offilters includes at least filters 1 a, 2 a, and 4 a as provided in Table2. In another embodiment, the first plurality of filters includes atleast filters 1 a, 3 a, and 5 a as provided in Table 2. In anotherembodiment, the first plurality of filters includes at least filters 2a, 3 a, and 4 a as provided in Table 2. In another embodiment, the firstplurality of filters includes at least filters 1 a and 2 a as providedin Table 2. In another embodiment, the first plurality of filtersincludes at least filters 1 a and 3 a as provided in Table 2. In anotherembodiment, the first plurality of filters includes at least filters 1 aand 4 a as provided in Table 2. In another embodiment, the firstplurality of filters includes at least filters 1 a and 5 a as providedin Table 2. In another embodiment, the first plurality of filtersincludes at least filters 2 a and 3 a as provided in Table 2. In anotherembodiment, the first plurality of filters includes at least filters 2 aand 4 a as provided in Table 2. In another embodiment, the firstplurality of filters includes at least filters 2 a and 5 a as providedin Table 2. In another embodiment, the first plurality of filtersincludes at least filters 3 a and 4 a as provided in Table 2. In anotherembodiment, the first plurality of filters includes at least filters 3 aand 5 a as provided in Table 2. In another embodiment, the firstplurality of filters includes at least filters 4 a and 5 a as providedin Table 2.

It is contemplated that, in some embodiments, any one or more of thefilters 216 provided in Table 2 will not be included in the firstplurality of filters. For example, in some embodiments, a characteristicassociated with a particular survey result will be informative whenqualifying a subject for one particular dihydropyridine-type calciumchannel blocker but not for another dihydropyridine-type calcium channelblocker.

Accordingly, it is contemplated that the first plurality of filtersincludes any sub-set of filters 216 provided in Table 2. Likewise, theskilled artisan may know of other filters 216, not provided in Table 2,which may be combined with any subset of the filters 216 provided inTable 2 to form the first plurality of filters results used in themethods described herein. For brevity, all possible combinations of thefilters 216 provided in Table 2 are not specifically delineated here.

Referring to blocks 420-422, in some embodiments the first plurality offilters comprises a pregnancy filter (e.g., first pregnancy filter 216-1in FIG. 3 and/or filter 1 a in Table 2). In some embodiments, thepregnancy filter is configured to be fired at least when the firstplurality of survey results indicates that the subject is pregnant orthe subject is breastfeeding. In some embodiments, the pregnancy filteris also configured to be fired when the subject is planning on becomingpregnant. When the pregnancy filter is fired, the subject is notpermitted to obtain the dihydropyridine-type calcium channel blockerpharmaceutical composition over-the-counter (e.g., the method isterminated without authorizing provision of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject). Forexample, the device transmits prompt 502, as illustrated in FIG. 5A, tothe subject and the device applies the subject's answer to the pregnancyfilter. If the subject's answer indicates that they are pregnant, theyare planning on being pregnant, they are breastfeeding, or they areplanning to breastfeeding, the pregnancy filter is fired, and the methodis terminated without authorizing provision of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject. Insome embodiments, the device transmits a message explaining whyauthorization was denied, e.g., message 504 illustrated in FIG. 5B.

Referring to blocks 424-426, in some embodiments the first plurality offilters comprises a dihydropyridine medication filter (e.g.,dihydropyridine medication filter 216-2 in FIG. 3 and/or filter 2 a inTable 2). The dihydropyridine medication filter is configured to befired at least when the first plurality of survey results indicates thatthe subject is taking (e.g., has a prescription for) adihydropyridine-type calcium channel blocker. In some embodiments, thedihydropyridine medication filter is fired when the first plurality ofsurvey results indicate that the subject is taking one or more ofamlodipine, isradipine, nisoldipine, or nifedipine. If thedihydropyridine medication filter is fired, the subject is not permittedto obtain the dihydropyridine-type calcium channel blockerpharmaceutical composition pharmaceutical composition over-the-counter(e.g., the method is terminated without authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject).

Referring to blocks 428-438 of FIGS. 4B and 4C, in some embodiments thefirst plurality of filters comprises a first blood pressure filter(e.g., first blood pressure filter 216-3 in FIG. 3 and/or filter 3 a inTable 2). The first blood pressure filter is configured to be fired atleast when the first plurality of survey results indicates that thesubject has normal blood pressure (e.g., a systolic blood pressure lessthan 120 mm Hg and a diastolic blood pressure less than 80 mm Hg) or thesubject has hypertension stage 2 (e.g., a systolic blood pressuregreater than or equal to 140 mm Hg or a diastolic blood pressure greaterthan or equal to 90 mm Hg). If the blood pressure filter is fired, thesubject is not permitted to obtain the dihydropyridine-type calciumchannel blocker pharmaceutical composition over-the-counter (e.g., themethod is terminated without authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject).

In some embodiments, the first blood pressure filter is fired when thefirst plurality of survey results indicates that the systolic bloodpressure of the subject is greater than a ceiling systolic pressure, thediastolic blood pressure of the subject is greater than a ceilingdiastolic pressure, or the systolic blood pressure of the subject isless than a floor systolic pressure and the diastolic blood pressure ofthe subject is less than a floor diastolic pressure. In someembodiments, the ceiling systolic pressure is 139 mm Hg, the ceilingdiastolic pressure is 89 mm Hg, the floor systolic pressure is 130 mmHg, and the floor diastolic pressure is 80 mm Hg. In some embodiments,the ceiling systolic pressure is 140 mm Hg, the ceiling diastolicpressure is 90 mm Hg, the floor systolic pressure is 129 mm Hg, and thefloor diastolic pressure is 79 mm Hg. In some embodiments, the bloodpressure cutoffs defining when the blood pressure filter is fired andwhen the blood pressure filter is not fired are set according to a setof healthcare guidelines, which may change over time, and/or vary on ajurisdiction-by-jurisdiction basis. For example, in the United States,the American College of Cardiology and the American Heart Associationcollaborated to provide guidance on management of high blood pressure.Whelton P K, et al., J Am Coll Cardiol., S0735-1097(17)41519-1 (2017),the contents of which are hereby expressly incorporated by reference.These guidelines change over time as medical research and advances intreatment better inform management of high blood pressure.

In some embodiments, e.g., when the first plurality of survey resultsindicate that the subject has elevated blood pressure but is nothypertensive (e.g., a systolic blood pressure in between 120 and 129 mmHg and a diastolic blood pressure less than 80 mm Hg), the first bloodpressure filter is fired, and advice is transmitted to the subject tomanage their blood pressure by eating healthy and exercising. In someembodiments, e.g., when the first plurality of survey results indicatethat the subject has hypertension stage two (e.g., a systolic bloodpressure greater than or equal to 140 mm Hg or a diastolic bloodpressure greater than or equal to 90 mm Hg), the first blood pressurefilter is fired and advice is transmitted to the subject to visit adoctor to discuss taking a prescription-strength blood pressuremedication. In some embodiments, e.g., when the first plurality ofsurvey results indicate that the subject is in hypertension crisis(e.g., a systolic blood pressure greater than 180 mm Hg and/or adiastolic blood pressure greater than 120 mm Hg), the first bloodpressure filter is fired, and advice is transmitted to the subject toseek emergency medical attention.

Referring to blocks 440-442 of FIG. 4C, in some embodiments the firstplurality of filters comprises an age filter (e.g., age filter 216-4 inFIG. 3 and/or filter 4 a in Table 2). In some embodiments, the agefilter is fired when the first plurality of survey results indicatesthat the subject is less than eighteen years old. If the age filter isfired, the subject is not permitted to obtain the dihydropyridine-typecalcium channel blocker pharmaceutical composition pharmaceuticalcomposition over-the-counter (e.g., the method is terminated withoutauthorizing provision of the dihydropyridine-type calcium channelblocker pharmaceutical composition to the subject).

In some embodiments, the age filter is fired when the first plurality ofsurvey results indicates that the subject has an age for which a risk ofan atherosclerotic cardiovascular disease (ASCVD) event cannot becalculated according to a predictive algorithm (e.g., a 10-year riskestimate for a hard ASCVD event using the pooled cohort equationsprovided in Goff, D C Jr. et al., Circulation (2013). For example, insome embodiments, the age filter is fired when the first plurality ofsurvey results indicates that the subject is less than forty years old,which would provide an incalculable risk using the equations in Goff etal.

Referring to blocks 444-452, in some embodiments the first plurality offilters comprises a pooled cohort equation filter (e.g., pooled cohortequation filter 216-5 in FIG. 3 and/or filter 5 a in Table 2). In someembodiments the pooled cohort equation filter incorporates the gender ofthe subject, the race of the subject, the age of the subject, the bloodpressure medication status of the subject, the total cholesterol levelof the subject, the HDL cholesterol count of the subject, the systolicblood pressure of the subject, the smoking status of the subject (e.g.,whether the subject currently smokes or has smoked in the past), and thediabetes status of the subject (e.g., whether the subject has Type-1diabetes, Type-2 diabetes, etc.) to derive a risk for atheroscleroticcardiovascular disease (e.g., a risk for experiencing an atheroscleroticcardiovascular disease (ASCVD) event within a certain timeframe, such asfive or ten years). In some embodiments, the pooled cohort equation alsoincorporates a familial history of premature heart or stroke (e.g., ahistory of heart attack or stroke before the age of forty-five, fifty,fifty-five, sixty, etc.). In some embodiments, the pooled cohortequation incorporates a high sensitive quantification of c-reactiveprotein (hsCRP) level of the subject. If the pooled cohort equationfilter is fired, the subject is not permitted to obtain thedihydropyridine-type calcium channel blocker pharmaceutical compositionpharmaceutical composition over-the-counter (e.g., the method isterminated without authorizing provision of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject).

In some embodiments, the first pooled cohort equation filter isconfigured to be fired at least when the first plurality of surveyresults indicates that, despite having hypertension stage 1 (e.g., asystolic blood pressure of 130 to 139 mm HG or a diastolic bloodpressure of 80 to 89 mm Hg) the subject has a risk for atheroscleroticdisease that falls below a minimum risk threshold (e.g., the subjectdoes not have a high enough risk of having an ASCVD event to justifytaking a dihydropyridine-type calcium channel blocker pharmaceuticalcomposition). In some embodiments, the risk for the atheroscleroticcardiovascular disease calculated using the pooled cohort equation is alifetime risk, a 5-year risk, or a 10-year risk. In some embodiments,the pooled cohort equation is implemented as a multivariable Coxproportional hazard regression.

In some embodiments, the pooled cohort equation filter is fired at leastwhen the first survey results indicate the subject has a 10-year riskfor atherosclerotic cardiovascular disease (e.g., a 10-year risk ofexperiencing an atherosclerotic cardiovascular disease (ASCVD) event)that is less than 10%, as determined by the pooled cohort equation. Insome embodiments, the first pooled cohort equation filter is alsoconfigured to be fired when one or more value provided by the subjectdoes not enable the pooled cohort equation to calculate an ASCVD eventrisk for the subject (e.g., a subject age of less than forty wouldprovide an incalculable risk using the equations in Goff et al.). Insome embodiments, the pooled cohort equation filter behaves as a filterof the second category class when a value provided by the subject doesnot enable the pooled cohort equation to calculate an ASCVD event risk.E.g., when the pooled cohort equation filter is fired for receiving avalue that is out of a range of values required to calculate an ASCVDevent risk, the device issues a warning to the subject (e.g., requiringthe subject discuss taking a dihydropyridine-type calcium channelblocker pharmaceutical composition with a medical professional) thatmust be acknowledged prior to being authorized to receive a provision ofthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition, rather than automatically terminating the process, as wouldbe done when a filter of the first category class is filtered. In someembodiments, the pooled cohort equation filter is fired when the firstsurvey results indicate the subject is younger than forty years old.

The pooled cohort equation estimates the probability of incurring a hardatherosclerotic cardiovascular disease (ASCVD) event in a given periodof time, such as in the next 5 years, the next 10 years, or in thelifetime of a subject. In some embodiments, the pooled cohort equationfor the pooled cohort equation filter is calculated using the guidelinesset forth in Goff, D C Jr, et al., J. Am. Coll. Cardiol., 63:2935-59(2014), the content of which is hereby incorporated by reference.Following the Goff et al. (Id.) calculation of the 10-year risk estimatefor a hard ASCVD event using the pooled cohort equations is done as aseries of steps. The natural log of the age of the subject, totalcholesterol, HDL-C, and systolic blood pressure are first calculatedwith the systolic blood pressure being either a treated or untreatedvalue. For example, calculation of the pooled cohort equations estimatethe probability of a Caucasian male subject 55 years of age with totalcholesterol 213 mg/dL, HDL-C 50 mg/dL, untreated systolic blood pressure120 mm Hg, nonsmoker, and without diabetes determine the probability ofa hard ASCVD event in the next 10 years using Goff Id. begins by firsttaking the natural log of the subject's age (4.01), the natural log ofthe subject's total cholesterol (5.36), the natural log of the subject'sHDL-C (3.91), and the natural log of the subject's systolic bloodpressure (4.79). These values are then multiplied by the coefficientsfrom the equation (“Coefficient” column of Table A of Goff Id.) for thespecific race-sex group of the individual to obtain “coefficient xvalues.” That is:

multiply the natural log of the subject's age (4.01) by the coefficient12.344 to obtain the “coefficient x value” of 49.47,

multiply the natural log of the subject's total cholesterol (5.36) bythe coefficient 11.853 to obtain the “coefficient x value” of 63.55,

multiply the natural log of the subject's HDL-C (3.91) by thecoefficient −7.990 to obtain the “coefficient x value” of −31.26, and

multiply the natural log of the subject's systolic blood pressure (4.79)by the coefficient 1.764 to obtain the “coefficient x value” of 8.45.

Any appropriate interaction terms are also calculated. Following GoffId., in the case of the Caucasian male subject 55 years of age, theinteraction terms are:

the Log Age (4.01) X Log total Cholesterol (5.36) multiplied by thecoefficient −2.664 to obtain the “coefficient x value” of −57.24 and

Log Age (4.01) X Log HDL-C (3.91) multiplied by the coefficient 1.769 toobtain the “coefficient x value” of 27.73.

The sum of these “coefficient x values” is then calculated for theindividual (49.47+63.55−31.26+8.45−57.24+27.73=60.69). The estimated10-year risk of a first hard ASCVD event is formally calculated as 1minus the baseline survival rate at 10 years for the sex/race (in thisexample Caucasian male), raised to the power of the exponent of the“Coefficient x Value” sum calculated above minus the race (Caucasian)and sex (Male) specific overall mean “Coefficient x Value” sum; or, inequation form:1−0.9144^(e) ^((60.69-61.18))where the number 0.9144 is the baseline survival rate at 10 years forCaucasian males from Goff Id., the number 60.69 is the “coefficient xvalue” calculated for the particular subject as detailed above, and thenumber 61.18 is the race (Caucasian) and sex (Male) specific overallmean “Coefficient x Value” from Goff Id. This equates to a 5.3%probability of a first hard ASCVD event within 10 years.

In some embodiments, the pooled cohort equation filter incorporates someor all of the characteristics listed in Table 7, e.g., as determinedfrom a set of survey results, to derive a subject risk foratherosclerotic cardiovascular disease. For example, in someembodiments, the first plurality of survey results includes 2, 3, 4, 5,6, 7, 8, 9, 10, or all 11 of the characteristics listed in Table 7. Thepooled cohort equation filter is fired when the subject's risk foratherosclerotic cardiovascular disease exceeds a threshold level ofrisk.

TABLE 7 Exemplary Characteristics Used for Pooled Cohort Equation FilterResult Exemplary Characteristics 1 a gender of the subject 2 an age ofthe subject 3 a total cholesterol level of the subject 4 a HDLcholesterol count of the subject 5 a systolic blood pressure of thesubject 6 a race of the subject 7 whether the subject is taking one ormore medications for hypertension 8 a smoking status of the subject 9 adiabetes status of the subject 10 whether the subject has a familyhistory of heart or stroke before the age of 60 11 a hsCRP level of thesubject

In one embodiment, the pooled cohort equation filter incorporates atleast survey results 1-9 as provided in Table 7. In another embodiment,the first survey results include at least survey results 1-10 asprovided in table 7. In another embodiment, the first survey resultsinclude at least survey results 1-9 and 11 as provided in Table 7. Inanother embodiment, the first survey results include at least surveyresults 1-11 as provided in Table 7.

In some embodiments, the pooled cohort equation used to calculate a riskof fatal cardiovascular disease for the pooled cohort equation filter iscalculated using the guidelines set forth in Perk J. et al., EuropeanGuidelines on cardiovascular disease prevention in clinical practice,European Heart Journal 33:1635-1701 (2012), which is hereby incorporatedby reference herein. In some embodiments, the pooled cohort equationfilter follows a low CVD risk SCORE chart, which incorporates the sex ofthe subject, the age of the subject, the total cholesterol level of thesubject, the systolic blood pressure of the subject, and a smokingstatus of the subject, as set forth in Perk J. et al., Supra. In someembodiments, the pooled cohort equation filter follows a high CVD riskSCORE chart, which incorporates the sex of the subject, the age of thesubject, the total cholesterol level of the subject, the systolic bloodpressure of the subject, and a smoking status of the subject, as setforth in Perk J. et al., Supra. In some embodiments, a conversion factoris used to convert a risk of fatal cardiovascular disease to a risk offatal plus nonfatal hard cardiovascular disease events, as set forth inCatapano A L et al., 2016 ESC/EAS Guidelines for the Management ofDyslipidaemias. Eur Heart J. 2016 Oct. 14; 37(39):2999-3058, which ishereby incorporated by reference herein.

In some embodiments, using the SCORE guidelines, the risk for the fatalcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and a first threshold value, e.g., a threshold valuewhich when the risk of the subject is determined to be less than firesthe filter, is a 3% risk. In some embodiments. In some embodiments, therisk for the fatal cardiovascular disease used in calculating the pooledcohort equation is a 10-year risk, and the first threshold value is a 5%risk. In some embodiments, the risk for the fatal cardiovascular diseaseused in calculating the pooled cohort equation is a 10-year risk, and asecond threshold value, e.g., a threshold value which when the risk ofthe subject is determined to be greater than fires the filter, is a 4%risk. In some embodiments, the risk for the fatal cardiovascular diseaseused in calculating the pooled cohort equation is a 10-year risk, andthe second threshold value is a 9% risk. In some embodiments, the riskfor the fatal cardiovascular disease used in calculating the pooledcohort equation is a 10-year risk, and the second threshold value is a14% risk. In some embodiments, the risk for the fatal cardiovasculardisease used in calculating the pooled cohort equation is a 10-yearrisk, and a threshold range, e.g., a threshold range which when thesubject is determined to have a risk above or below the range fires thefilter, is a 2-14% risk. In some embodiments, the risk for the fatalcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and the threshold range is a 3-14% risk. In someembodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and thethreshold range is a 5-14% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 10-14% risk. Insome embodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and thethreshold range is a 2-9% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 3-9% risk. Insome embodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and thethreshold range is a 5-9% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 2-4% risk. Insome embodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and thethreshold range is a 3-4% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 2-3% risk. Insome embodiments, lipid lowering therapy is not indicated, e.g., afilter of the second class type is fired, when it is determined thesubject has less than a 5% ten-year risk of fatal cardiovasculardisease.

In some embodiments, the pooled cohort equation used to calculate a riskof a cardiovascular disease-related death for the pooled cohort equationfilter is calculated using the guidelines set forth in Teramoto et al.,Japan Atherosclerosis Society. Executive summary of the JapanAtherosclerosis Society (JAS) guidelines for the diagnosis andprevention of atherosclerotic cardiovascular diseases in Japan-2012version, J Atheroscler Thromb., 2013; 20(6):517-23, which is herebyincorporated by reference herein. In some embodiments, the pooled cohortequation filter follows the NIPPON DATA80 absolute risk assessmentcharts, which incorporate the sex of the subject, the age of thesubject, the total cholesterol level of the subject, the systolic bloodpressure of the subject, and a smoking status of the subject, as setforth in Teramoto et al., Supra. In some embodiments, the pooled cohortequation also incorporates a glucose level of the subject.

In some embodiments, using the NIPPON DATA80 guidance, the risk for thecoronary artery death used in calculating the pooled cohort equation isa 10-year risk, and a first threshold value, e.g., a threshold valuewhich when the risk of the subject is determined to be less than firesthe filter, is a 0.5% risk. In some embodiments, the risk for the fatalcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and the first threshold value is a 1% risk. In someembodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and the firstthreshold value is a 2% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and a second threshold value, e.g., athreshold value which when the risk of the subject is determined to begreater than fires the filter, is a 1% risk. In some embodiments, therisk for the fatal cardiovascular disease used in calculating the pooledcohort equation is a 10-year risk, and the second threshold value is a2% risk. In some embodiments, the risk for the fatal cardiovasculardisease used in calculating the pooled cohort equation is a 10-yearrisk, and the second threshold value is a 5% risk. In some embodiments,the risk for the fatal cardiovascular disease used in calculating thepooled cohort equation is a 10-year risk, and the second threshold valueis a 10% risk. In some embodiments, the risk for the fatalcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and a threshold range, e.g., a threshold range whichwhen the subject is determined to have a risk above or below the rangefires the filter, is a 0.5-10% risk. In some embodiments, the risk forthe fatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 1-10% risk. Insome embodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and thethreshold range is a 2-10% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 5-10% risk. Insome embodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and thethreshold range is a 0.5-5% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 1-5% risk. Insome embodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and thethreshold range is a 2-5% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 0.5-2% risk. Insome embodiments, the risk for the fatal cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and thethreshold range is a 1-2% risk. In some embodiments, the risk for thefatal cardiovascular disease used in calculating the pooled cohortequation is a 10-year risk, and the threshold range is a 0.5-1% risk.

In some embodiments, the pooled cohort equation used to calculate a riskof atherosclerotic cardiovascular disease for the pooled cohort equationfilter is calculated using the guidelines set forth in Yang X. et al.,Predicting the 10-Year Risks of Atherosclerotic Cardiovascular Diseasein Chinese Population: The China-PAR Project (Prediction for ASCVD Riskin China). Circulation. 2016 Nov. 8; 134(19):1430-1440, which is herebyincorporated by reference herein. In some embodiments, the pooled cohortequation filter follows the China-PAR gender specific equations, whichincorporate the sex of the subject (e.g., to determine which equation touse), the age of the subject, the systolic blood pressure of thesubject, a blood pressure treatment status of the subject, the totalcholesterol level of the subject, a smoking status of the subject, adiabetes mellitus status of the subject, the waist circumference of thesubject, a geographic residential-region of the subject (e.g., forChinese residents only, either northern China or southern China), anurbanization residential-region of the subject (e.g., for men residingin China only, either urban or rural), and family history ofatherosclerotic cardiovascular disease (e.g., for men only), as setforth in Yang X. et al., Supra and at Supplemental Information. In someembodiments, the pooled cohort equation also incorporates an HDLcholesterol level of the subject and/or a cholesterol treatment statusof the subject.

In some embodiments, using the China-PAR guidance, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 10-year risk, and a first threshold value, e.g., athreshold value which when the risk of the subject is determined to beless than fires the filter, is a 5% risk. In some embodiments, the riskfor the atherosclerotic cardiovascular disease used in calculating thepooled cohort equation is a 10-year risk, and the first threshold valueis a 7.5% risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and a second threshold value, e.g., a threshold valuewhich when the risk of the subject is determined to be greater thanfires the filter, is a 7.5% risk. In some embodiments, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 10-year risk, and the second threshold value is a10% risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and a threshold range, e.g., a threshold range whichwhen the subject is determined to have a risk above or below the rangefires the filter, is a 5-10% risk. In some embodiments, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 10-year risk, and the threshold range is a 7.5-10%risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and the threshold range is a 5-7.5% risk.

In some embodiments, the pooled cohort equation used to calculate a riskof atherosclerotic cardiovascular disease for the pooled cohort equationfilter 222-2 is calculated using the guidelines set forth in NationalVascular Disease Prevention Alliance, Guidelines for the management ofabsolute cardiovascular disease risk, 2012, which is hereby incorporatedby reference herein. In some embodiments, the pooled cohort equationfilter follows the Australian cardiovascular risk charts, whichincorporate the sex of the subject, the age of the subject, the systolicblood pressure of the subject, the ratio of total cholesterol to HDLlevels of the subject, and a smoking status of the subject, as set forthin Absolute cardiovascular disease risk management: Quick referenceguide for health professionals, 2012, National Stroke Foundation. Insome embodiments, the pooled cohort equation also incorporates thedecent of the subject (e.g., in Australia only, for Aboriginal, TorresStrait Islander, or other populations).

In some embodiments, using the Australian cardiovascular risk charts,the risk for the atherosclerotic cardiovascular disease used incalculating the pooled cohort equation is a 5-year risk, and a firstthreshold value, e.g., a threshold value which when the risk of thesubject is determined to be less than fires the filter, is a 5% risk. Insome embodiments, the risk for the atherosclerotic cardiovasculardisease used in calculating the pooled cohort equation is a 5-year risk,and the first threshold value is a 10% risk. In some embodiments, therisk for the atherosclerotic cardiovascular disease used in calculatingthe pooled cohort equation is a 5-year risk, and the first thresholdvalue is a 16% risk. In some embodiments, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 5-year risk, and the first threshold value is a 20%risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 5-year risk, and the first threshold value is a 25% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 5-year risk, and asecond threshold value, e.g., a threshold value which when the risk ofthe subject is determined to be greater than fires the filter, is a 30%risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 5-year risk, and the second threshold value is a 25% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 5-year risk, and thesecond threshold value is a 20% risk. In some embodiments, the risk forthe atherosclerotic cardiovascular disease used in calculating thepooled cohort equation is a 5-year risk, and the second threshold valueis a 16% risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 5-year risk, and the second threshold value is a 10% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 5-year risk, and thesecond threshold value is a 5% risk. In some embodiments, the risk forthe atherosclerotic cardiovascular disease used in calculating thepooled cohort equation is a 5-year risk, and a threshold range, e.g., athreshold range which when the subject is determined to have a riskabove or below the range fires the filter, is a 5-30% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 5-year risk, and thethreshold range is a 10-30% risk. In some embodiments, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 5-year risk, and the threshold range is a 16-30%risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 5-year risk, and the threshold range is a 20-30% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 5-year risk, and thethreshold range is a 25-30% risk. In some embodiments, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 5-year risk, and the threshold range is a 5-25%risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 5-year risk, and the threshold range is a 10-25% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 5-year risk, and thethreshold range is a 16-25% risk. In some embodiments, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 5-year risk, and the threshold range is a 20-25%risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 5-year risk, and the threshold range is a 5-20% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 5-year risk, and thethreshold range is a 10-20% risk. In some embodiments, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 5-year risk, and the threshold range is a 16-20%risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 5-year risk, and the threshold range is a 5-16% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 5-year risk, and thethreshold range is a 10-16% risk. In some embodiments, the risk for theatherosclerotic cardiovascular disease used in calculating the pooledcohort equation is a 5-year risk, and the threshold range is a 5-10%risk.

In some embodiments, the pooled cohort equation used to calculate a riskof atherosclerotic cardiovascular disease for the pooled cohort equationfilter 222-2 is calculated using the guidelines set forth in Anderson TJ et al., 2016 Canadian Cardiovascular Society Guidelines for theManagement of Dyslipidemia for the Prevention of Cardiovascular Diseasein the Adult, Can J Cardiol. 2016 November; 32(11):1263-1282, which ishereby incorporated by reference herein. In some embodiments, the pooledcohort equation filter follows a Framingham Heart Study Risk Scoreequation (FRS), which incorporates the sex of the subject, the age ofthe subject, the systolic blood pressure of the subject, a bloodpressure treatment status of the subject, the total cholesterol level ofthe subject, and an HDL cholesterol level of the subject, a smokingstatus of the subject, a diabetes mellitus status of the subject, and aCVD event incident status of the subject, as set forth in D'Agostino R BSr et al., General cardiovascular risk profile for use in primary care:the Framingham Heart Study. Circulation. 2008 Feb. 12; 117(6):743-53,which is hereby incorporated by reference herein. In some embodiments,the pooled cohort equation filter follows a modified Framingham HeartStudy Risk Score equation (FRS), which incorporates the sex of thesubject, the age of the subject, the systolic blood pressure of thesubject, a blood pressure treatment status of the subject, the totalcholesterol level of the subject, and an HDL cholesterol level of thesubject, a smoking status of the subject, a diabetes mellitus status ofthe subject, and a CVD event incident status of the subject, and afamily history status of premature cardiovascular disease, as set forthin Anderson T J et al., Supra. In some embodiments, the pooled cohortequation filter follows a Cardiovascular Life Expectancy Model (CLEM),as set forth in Grover S A et al., Estimating the benefits of modifyingrisk factors of cardiovascular disease: a comparison of primary vssecondary prevention. Arch Intern Med. 1998 Mar. 23; 158(6):655-62,which is hereby incorporated by reference herein. Referring to block428, in some embodiments, using the Canadian Cardiovascular Societyguidance, the risk for the atherosclerotic cardiovascular disease usedin calculating the pooled cohort equation is a 10-year risk, and a firstthreshold value, e.g., a threshold value which when the risk of thesubject is determined to be less than fires the filter, is a 5% risk. Insome embodiments, the risk for the atherosclerotic cardiovasculardisease used in calculating the pooled cohort equation is a 10-yearrisk, and the first threshold value is a 10% risk. In some embodiments,the risk for the atherosclerotic cardiovascular disease used incalculating the pooled cohort equation is a 10-year risk, and a secondthreshold value, e.g., a threshold value which when the risk of thesubject is determined to be greater than fires the filter, is a 20%risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and the second threshold value is a 10% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 10-year risk, and athreshold range, e.g., a threshold range which when the subject isdetermined to have a risk above or below the range fires the filter, isa 5-20% risk. In some embodiments, the risk for the atheroscleroticcardiovascular disease used in calculating the pooled cohort equation isa 10-year risk, and the threshold range is a 10-20% risk. In someembodiments, the risk for the atherosclerotic cardiovascular diseaseused in calculating the pooled cohort equation is a 10-year risk, andthe threshold range is a 5-10% risk.

In some embodiments, a probability of the occurrence of a hard ASCVDevent in a given period of time (e.g., within the next 10 years), e.g.,as calculated above, is modified by considering one or both of thefamilial history of the subject for premature heart attacks or strokesand the hsCRP level of the subject. This inclusion is to reduce alikelihood of over-predicting adverse events, e.g., in subjects withouta familial history of adverse events and/or with healthy hsCRP levels.

In some embodiments, e.g., when the first survey results indicate thatthe subject is at least 80 years old, that the subject has had anatherosclerotic cardiovascular event, or that the subject has had aheart procedure, the device bypasses the pooled cohort equation filter(e.g., even if the first plurality of survey results indicates that thesubject has an ASCVD risk falling below a minimum threshold risk, orthat the subject has an age rendering calculation of an ASCVD riskimpossible, the pooled cohort equation filter is not fired). Forexample, as illustrated in FIG. 7 , in response to determining that thesubject has an ASCVD history (e.g., has experienced an ASCVD event orhad a heart procedure) at 720 or determining that the subject is atleast 80 years of age at 730, the device generates a record of anexempting condition (e.g., 760-1 or 760-2) and then, prior to applyingone or more survey results to the pooled cohort equation at 765, thedevice determines whether an exempting condition is present at 762. If acondition is present, pooled cohort equation filter 765 is bypassed andthe device proceeds to liver disease filter 770. In some embodiments,the exemption record is a record of survey result, e.g., the devicepre-checks earlier recorded survey results associated with ASCVD historyand age prior to proceeding with pooled cohort equation filter 765. Insome embodiments, the exemption record is a record separate from thesurvey result that indicates the exempting condition, and the devicechecks for separate records indicating the presence of an exemptingcondition before proceeding with pooled cohort equation filter 765.

Referring to block 452 of FIG. 4D, in some embodiments the firstplurality of survey results further comprises whether the subject isallergic to the dihydropyridine-type calcium channel blockerpharmaceutical composition, and the first plurality of filters includesan adverse reaction filter. The adverse reaction filter is fired whenthe first survey results indicate that the subject is allergic to thedihydropyridine-type calcium channel blocker pharmaceutical composition.In some embodiments, the adverse reaction filter is fired when the firstsurvey results indicate that the subject has developed an adversereaction to a dihydropyridine-type calcium channel blocker medication inthe past. In some embodiments, the adverse reaction filter is fired whenthe first survey results indicate that the subject has developed anadverse reaction to any dihydropyridine-type calcium channel blockerpharmaceutical composition in the past.

Referring to block 454 of FIG. 4D, the method also includes running allor a portion of the first survey results against a second plurality offilters of a second category class 220. When a respective filter in thesecond plurality of filters is fired, the subject is provided with awarning 226 corresponding to the respective filter (e.g., filter warning228-4 corresponds to filter 222-4). In some embodiments, the warning 226is provided as a next step, e.g., prior to applying survey results toany subsequent filters, after the corresponding filter is fired. Forexample, with respect to FIG. 7C, in some embodiments, e.g., when theliver disease filter is triggered at 770, the device would provide thesubject with a warning prior to proceeding to the drug interactionfilter at 775, e.g., requiring the subject confirm they have discussedtheir history of liver disease with a health care provider and thehealthcare provider still recommends taking a dihydropyridine-typecalcium channel blocker pharmaceutical composition. In some embodimentsthe warning 226 is provided after applying survey results to allsubsequent filters. For example, as illustrated in FIG. 7C, in someembodiments, e.g., when the liver disease filter is triggered at 770,the device would proceed to the drug interaction filter at 775 prior totransmitting a warning to the subject, and then transmit all warningscorresponding to filters of the second category class, at 784, aftersurvey results have been applied to all subsequent filters.

In some embodiments, the second plurality of filters 222 of the secondcategory class 220 includes the filters listed in Table 3.

TABLE 3 Exemplary Second Plurality of Filters of the Second CategoryClass Filter Exemplary Criteria 1a a first liver disease filter 2a afirst drug interaction filter

It is contemplated that, in some embodiments, any one or more of thefilters provided in Table 3 will not be included in the second pluralityof filters. For example, in some embodiments, a characteristicassociated with a particular survey result will be informative whenqualifying a subject for one particular dihydropyridine-type calciumchannel blocker pharmaceutical composition but not for anotherdihydropyridine-type calcium channel blocker pharmaceutical composition.Accordingly, it is contemplated that the second plurality of filtersincludes any sub-set of filters provided in Table 3. Likewise, theskilled artisan may know of other filters, not provided in Table 3, thatmay be combined with any subset of the filters provided in Table 3 toform the second plurality of filters results used in the methodsdescribed herein.

Referring to block 456, in some embodiments, the second plurality offilters includes a liver disease filter (e.g., first liver diseasefilter 222-1 in FIG. 3 and/or filter 1 a in Table 3). The liver diseasefilter is configured to be fired at least when the first plurality ofsurvey results indicate that the subject has had a liver problem. Insome embodiments, liver problems that are capable of triggering thefirst liver disease filter include impaired hepatic function, acuteliver failure, and cholestasis. When the liver disease filter is fired,the device transmits a warning corresponding to the liver diseasefilter, and requires the user to acknowledge the warning beforeauthorizing a provision of the dihydropyridine-type calcium channelblocker pharmaceutical composition.

Referring to block 458, in some embodiments, the second plurality offilters includes a drug interaction filter (e.g., first drug interactionfilter 222-2 in FIG. 3 and/or filter 2 a in Table 3). The druginteraction filter is configured to be fired at least when the firstplurality of survey results indicates that the subject is taking amedication that interacts with the dihydropyridine-type calcium channelblocker pharmaceutical composition. When the drug interaction filter isfired, the device transmits a warning corresponding to the druginteraction filter, and requires the user to acknowledge the warningbefore authorizing a provision of the dihydropyridine-type calciumchannel blocker pharmaceutical composition.

In some embodiments, the drug capable of firing the drug interactionfilter is one of simvastatin, cyclosporine, tacrolimus, sildenafil, or aCYP3A inhibitor. In some embodiments, the CYP3A inhibitor includesdiltiazem, itraconazole, and clarithromycin. In some embodiments,medications that are capable of firing the drug interaction filterinclude propranolol, cimetidine, rifampicin, and fentanyl anesthesia. Insome embodiments, these predetermined medications include but are notlimited to digoxin, quinidine, coumarin anticoagulants, CYP3A4 inducers,phenytoin, and grapefruit juice and/or grapefruit extract.

The identity of drugs that are capable of triggering the druginteraction filter vary from one dihydropyridine-type calcium channelblocker to another dihydropyridine-type calcium channel blocker. Theskilled artisan will know of drugs that interact with onedihydropyridine-type calcium channel blocker but not another. Inclusionof a drug within the drug interaction filter is dependent upon theidentity and/or the dosage of the dihydropyridine-type calcium channelblocker pharmaceutical composition being authorized for over-the-counteruse.

In some implementations, a drug that interacts with adihydropyridine-type calcium channel blocker pharmaceutical compositionis included within a filter 216 in the first filter category class 214,rather than within drug interaction filter 222 of the second filtercategory class 220. For example, according to some implementations, aparticular drug included in drug-interaction filter 222 (e.g., as a riskfactor) for a first dihydropyridine-type calcium channel blockerpharmaceutical composition, but included in a filter in the firstplurality of filters (e.g., as a contraindication) for a seconddihydropyridine-type calcium channel blocker pharmaceutical composition.However, a person skilled in the art will know whether to include acertain drug within drug interaction filter 222 or as a separate filter216 in the first plurality of filters, based on the severity and risk ofthe drug interaction with the particular identity and dosage of thedihydropyridine-type calcium channel blocker being authorized forover-the-counter use.

Referring to block 462, in some embodiments the warning 226corresponding to a respective filter 222 in the second plurality offilters includes a prompt for the subject to indicate whether they havediscussed the risk factor underlying the respective filter in the secondplurality of filters that was fired with a health care practitioner(e.g., a licensed medical practitioner), e.g., and the health carepractitioner indicated that the subject should take adihydropyridine-type calcium channel blocker pharmaceutical compositionin view of the underlying risk factor. Accordingly, acknowledgement isobtained from the subject when the subject indicates that they havediscussed the risk factor underlying the respective filter in the secondplurality of filters that was fired with a health care provider. Forexample, message 602 in FIG. 6 illustrates a warning that is generic toany fired filters. In some embodiments, the warning is specific to aparticular filter (e.g., filter warning 226 in FIG. 2 ), e.g.,communicating to the user why the filter was fired.

In some embodiments, an acknowledgment from the user is verified by thehealth care practitioner (e.g., the method requires verification inorder for authorization of the provision of the dihydropyridine-typecalcium channel blocker pharmaceutical composition), e.g., in order toverify an accuracy of the survey results of the subject. In someembodiments, e.g., when the acknowledgment is verified by the heath carepractitioner, the subject is deemed a trusted subject, such thatverification of future results is not required.

Referring to block 464 of FIG. 4D, the method includes obtainingacknowledgment from the subject for any warning 226 issued to thesubject by any filter 222 in the second plurality of filters. If afilter 216 in the first plurality of filters fires, the subject isdenied access to the over-the-counter dihydropyridine-type calciumchannel blocker pharmaceutical composition.

Blocks 466-476. Referring to block 466 of FIG. 4E, the process controlproceeds to the fulfillment process when no filter 216 in the firstplurality of filters has been fired and the subject has acknowledgedeach warning 226 associated with each filter 222 in the second pluralityof filters that was fired. In some embodiments, the fulfillment processcomprises storing an indication in a user profile 234 of an initialorder date and/or destination for the dihydropyridine-type calciumchannel blocker pharmaceutical composition. The initial order date isutilized, for example, to verify at least a refill status of a provisionof the dihydropyridine-type calcium channel blocker. The initial orderdate is also utilized, for example, to verify at least an elapsed periodof time between an initial order and a future re-order. Suchverification is required in order to ensure that certain tests (e.g.,blood pressure tests) are taken regularly.

The fulfillment process further comprises communicating anover-the-counter drug facts label 230 for the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject. Insome embodiments, the drug facts label is communicated to the subject inreal-time, e.g., within the same user interface as used for thequalification process. In some embodiments, the over-the-counter drugfacts label 230 specifies what the dihydropyridine-type calcium channelblocker pharmaceutical composition is for (e.g., to lower bloodpressure, to treat heart disease, etc.) and any risks associated withtaking the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition (e.g., drug-drug interactions, pharmacokinetic interactions,adverse reactions, etc.) For instance, in some embodiments, uponconfirmation from the subject that the over the counter drug facts labelhas been received and read, the subject is authorized for provision of adosage of from 1 mg to 10 mg of dihydropyridine-type calcium channelblocker no more than once per day (block 470). In another exampleembodiment upon confirmation from the subject that the over the counterdrug facts label has been received and read, the subject is authorizedfor provision of a dosage of from 2.5 mg to 5 mg of dihydropyridine-typecalcium channel blocker no more than once per day (block 472).

In some embodiments, upon confirmation from the subject that the overthe counter drug facts label has been received and read, the subject isauthorized for provision of a dosage of from 1 mg to 10 mg of amlodipineno more than once per day. In some embodiments, upon confirmation fromthe subject that the over the counter drug facts label has been receivedand read, the subject is authorized for provision of a dosage of from2.5 mg to 10 mg of amlodipine no more than once per day. In someembodiments, upon confirmation from the subject that the over thecounter drug facts label has been received and read, the subject isauthorized for provision of a dosage of from 2.5 mg to 5 mg ofamlodipine no more than once per day. In some embodiments, thedihydropyridine-type calcium channel blocker pharmaceutical compositioncomprises amlodipine besylate.

In some embodiments, upon confirmation from the subject that the overthe counter drug facts label has been received and read, the subject isauthorized for provision of a dosage of from 15 mg to 90 mg ofnifedipine no more than once per day. In some embodiments, uponconfirmation from the subject that the over the counter drug facts labelhas been received and read, the subject is authorized for provision of adosage of from 30 mg to 60 mg of nifedipine no more than once per day.In some embodiments, upon confirmation from the subject that the overthe counter drug facts label has been received and read, the subject isauthorized for provision of a dosage of 30 mg of nifedipine no more thanonce per day. In some embodiments, upon confirmation from the subjectthat the over the counter drug facts label has been received and read,the subject is authorized for provision of a dosage of 60 mg ofnifedipine no more than once per day.

In some embodiments, upon confirmation from the subject that the overthe counter drug facts label has been received and read, the subject isauthorized for provision of a dosage of from 2.5 mg to 20 mg ofisradipine no more than once per day. In some embodiments, uponconfirmation from the subject that the over the counter drug facts labelhas been received and read, the subject is authorized for provision of adosage of from 2.5 mg to 10 mg of isradipine no more than once per day.In some embodiments, upon confirmation from the subject that the overthe counter drug facts label has been received and read, the subject isauthorized for provision of a dosage of from 5 mg to 10 mg of isradipineno more than once per day. In some embodiments, upon confirmation fromthe subject that the over the counter drug facts label has been receivedand read, the subject is authorized for provision of a dosage of 5 mg ofisradipine no more than once per day. In some embodiments, uponconfirmation from the subject that the over the counter drug facts labelhas been received and read, the subject is authorized for provision of adosage of 10 mg of isradipine no more than once per day.

In some embodiments, upon confirmation from the subject that the overthe counter drug facts label has been received and read, the subject isauthorized for provision of a dosage of from 25 mg to 250 mg ofnisoldipine no more than once per day. In some embodiments, uponconfirmation from the subject that the over the counter drug facts labelhas been received and read, the subject is authorized for provision of adosage of from 50 mg to 200 mg of nisoldipine no more than once per day.In some embodiments, upon confirmation from the subject that the overthe counter drug facts label has been received and read, the subject isauthorized for provision of a dosage of from 100 mg to 200 mg ofnisoldipine no more than once per day. In some embodiments, uponconfirmation from the subject that the over the counter drug facts labelhas been received and read, the subject is authorized for provision of adosage of 200 mg of nisoldipine no more than once per day. In someembodiments, upon confirmation from the subject that the over thecounter drug facts label has been received and read, the subject isauthorized for provision of a dosage of 100 mg of nisoldipine no morethan once per day.

Referring to block 474 of FIG. 4E, in some embodiments the fulfillmentprocess further comprises authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject. The authorization occurs upon confirmation from thesubject that the over-the-counter drug facts label 230 has been receivedand read by the subject. In some embodiments, this authorizationincludes a destination associated with the subject. In some embodiments,the destination associated with the subject is stored in the userprofile 234. In some embodiments, the destination associated with thesubject is a physical address including a street address, a Post Officebox, a pharmacy associated with the subject, a health care providerassociated with the subject, and/or one or more coordinates (e.g.,longitude, latitude, elevation). In some embodiments, the provision ofthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition to the subject comprises shipping the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the physicaladdress associated with the subject (block 476). In some embodiments,the provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject comprises shipping thedihydropyridine-type calcium channel blocker pharmaceutical compositionto a pharmacy associated and/or a location associated with a health careprovider of the subject and/or an office of a medical practitionerassociated with the subject.

Blocks 460-508. Referring to blocks 460-508 of FIGS. 4F-4I, are-fulfillment process will be described infra. In some embodiments, thepresent disclosure provides a method for qualifying a subject for arefill of a dihydropyridine-type calcium channel blocker pharmaceuticalcomposition. In some embodiments, the qualification for a refill of thedihydropyridine-type calcium channel blocker pharmaceutical compositionfollows an initial qualification of the subject, as described herein. Insome embodiments, the qualification for a refill of thedihydropyridine-type calcium channel blocker pharmaceutical compositionfollows issuance of a prescription to the subject for thedihydropyridine-type calcium channel blocker pharmaceutical composition.For example, in some embodiments, a subject who is new to thequalification process is asked whether they previously received aprescription for the dihydropyridine-type calcium channel blockerpharmaceutical composition and, if the subject indicates that they havenot previously received a prescription, the subject is directed to aninitial qualification method and, if the subject indicates that theyhave previously received a prescription, the subject is directed to therefill qualification method, e.g., as described below.

Referring to block 460 of FIG. 4F, in some embodiments a re-fulfillmentprocedure is performed. The re-fulfillment procedure is responsive toreceiving a re-order request from the subject for thedihydropyridine-type calcium channel blocker pharmaceutical composition.In some embodiments, a prompt to initiate the re-fulfillment procedureis sent to user device 102 associated with the subject after apredetermined amount of time associated with a duration of dosagespreviously delivered to the subject (e.g., the user is reminded tofulfill their order of the dihydropyridine-type calcium channel blockerpharmaceutical composition just before, or just after, the user isscheduled to run out of a previously delivered provision.

Referring to blocks 480-482, in some embodiments the re-fulfillmentprocedure comprises conducting a second survey of the subject. Thesecond survey is configured to obtain a second plurality of surveyresults. These results are derived from corresponding survey questions(e.g., the device transmits one or more survey questions to the user,prompting a response, and then receives a response to the one or moresurvey questions back from the subject). In some embodiments, the secondplurality of survey results include some or all of the characteristicslisted in Table 4. For example, in some embodiments, the secondplurality of survey results includes 1, 2, 3, 4, or all 5 of thecharacteristic listed in Table 4. In one embodiment, the second surveyquestions and results include at least characteristics 1-4 as providedin Table 4.

In some embodiments, the second survey results comprises at least one ofwhether the subject is one of pregnant, breastfeeding, or planning tobecome pregnant (e.g., responsive to a survey question that isassociated with and/or applied to (815) a pregnancy filter of a firstcategory class 214-2), whether the subject has experienced anatherosclerotic cardiovascular event or had a heart procedure sincereceiving their last provision of the dihydropyridine-type calciumchannel blocker pharmaceutical composition (e.g., responsive to a surveyquestion that is associated with and/or applied to (820) anatherosclerotic cardiovascular event filter of a second category class220-2), whether the subject has started taking a medication thatinteracts with the dihydropyridine-type calcium channel blockerpharmaceutical composition since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition(e.g., responsive to a survey question that is associated with and/orapplied to (825) a drug interaction filter of a second category class220-2), and whether the subject has developed a liver problem sincereceiving their last provision of the dihydropyridine-type calciumchannel blocker pharmaceutical composition (e.g., responsive to a surveyquestion that is associated with and/or applied to (830) a liver diseasefilter of a second category class 220-2).

In some embodiments, the second survey includes questions that elicitresponses providing some or all of the characteristics listed in Table4. In some embodiments, the second survey includes questionscorresponding to each of the survey results required for the methodsdescribed herein. In other embodiments, the second survey includesquestions corresponding to only a subset of the survey results requiredfor the methods described herein. In such embodiments, other surveyresults required for the methods described herein are acquired throughother means (e.g., upon registration/subscription for a serviceassociated with qualifying the subject for over-the-counter medication,from a healthcare provider, from a prior survey, from a databaseassociated with a pharmacy, etc.) For example, in some embodiments, thesubject provides a personal medical identification associated with aninsurer, a hospital, or other healthcare provider and information aboutthe subject required for the methods described herein, e.g., one or moresurvey results, is acquired from a preexisting database associated withthe personal medical identification (e.g., a last cholesterol or bloodpressure measurement determined for the subject).

TABLE 4 Exemplary Second Survey Questions Result ExemplaryCharacteristics 1 whether the subject is one of (i) pregnant, (ii)breastfeeding, or (iii) planning to become pregnant 2 whether thesubject has experienced an atherosclerotic cardiovascular event or had aheart procedure since receiving their last provision of thedihydropyridine- type calcium channel blocker pharmaceutical composition3 whether the subject has started taking a medication that interactswith the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition4 whether the subject has developed a liver problem since receivingtheir last provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition 5 a blood pressure status of the subject 6whether the subject has developed a side effect associated with thedihydropyridine-type calcium channel blocker since receiving their lastprovision of the dihydropyridine-type calcium channel blockerpharmaceutical composition

It is contemplated that, in some embodiments, any one or more of thesurvey questions provided in Table 4 will not be included in the secondsurvey (e.g., will not be used for the reassessment). For example, insome embodiments, a characteristic associated with a particular surveyquestions will be informative when qualifying a subject for oneparticular dihydropyridine-type calcium channel blocker but not foranother dihydropyridine-type calcium channel blocker. For instance, asurvey question is queried for isradipine qualifying surveys but not fornisoldipine qualifying surveys. The skilled artisan will recognize thatdifferent dihydropyridine-type calcium channel blockers carry differentrisk and drug interaction profiles. Accordingly, survey informationrequired for qualifying a subject for access to one dihydropyridine-typecalcium channel blocker with a known adverse drug interaction may not benecessary for qualifying the same subject for access to a seconddihydropyridine-type calcium channel blocker.

Accordingly, it is contemplated that the second survey questions elicitresponses to any sub-set of survey results provided in Table 4. Forbrevity, all possible combinations of the characteristics provided inTable 4 are not specifically delineated here. However, the skilledartisan will easily be able to envision any particular subset of surveyquestions designed to elicit responses to any subset of characteristicsprovided in Table 4. Likewise, the skilled artisan may know of othersurvey questions, not provided in Table 4, that may be combined with anysubset of the survey questions provided in Table 4 to form the secondsurvey questions used in the methods described herein.

Referring to block 484 of FIG. 4G, all or a portion the results are runagainst a third plurality of filters of the first category class. When arespective filter in the third plurality of filters is fired (e.g., whena survey result indicates that a triggering condition 218 has been met),the subject is deemed not qualified for the dihydropyridine-type calciumchannel blocker pharmaceutical composition and the method is terminatedwithout delivery of the dihydropyridine-type calcium channel blockerpharmaceutical composition.

Referring to blocks 486-500, specific filters in the third plurality offilters and their exemplary triggering conditions that cause thecorresponding filter to fire are detailed.

In some embodiments, the third plurality of filters of the firstcategory class includes some or all of the filters listed in Table 5.For example, in some embodiments, the third plurality of filtersincludes one or both of the filters listed in Table 5.

TABLE 5 Exemplary Third Plurality of Filters of the First Category ClassFilter Exemplary Criteria 1a a second pregnancy filter 2a a second bloodpressure filter

In one embodiment, the third plurality of filters includes at leastfilters 1 a-2 a as provided in Table 5. In another embodiment, the thirdplurality of filters includes at least filter 1 a as provided in Table5. In another embodiment, the first plurality of filters includes atleast filter 2 a as provided in Table 5.

It is contemplated that, in some embodiments, any one or more of thefilters provided in Table 5 will not be included in the third pluralityof filters. For example, in some embodiments, a characteristicassociated with a particular survey result will be informative whenqualifying a subject for one particular dihydropyridine-type calciumchannel blocker but not for another dihydropyridine-type calcium channelblocker. Likewise, the skilled artisan may know of other filters, notprovided in Table 5, which may be combined with any subset of thefilters provided in Table 2 to form the third plurality of filtersresults used in the methods described herein. For brevity, all possiblecombinations of the filters provided in Table 5 are not specificallydelineated here.

Referring to block 486, in some embodiments the third plurality offilters comprises a second pregnancy filter, e.g., as described above inrelation to the first pregnancy filter 216-1. In some embodiments, thepregnancy filter is configured to be fired at least when the secondplurality of survey results indicates that the subject is pregnant orthe subject is breastfeeding. In some embodiments, the pregnancy filteris also configured to be fired when the subject is planning on becomingpregnant. When the pregnancy filter is fired, the subject is notpermitted to obtain the dihydropyridine-type calcium channel blockerpharmaceutical composition over-the-counter (e.g., the method isterminated without authorizing re-provision of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject).

Referring to blocks 488-494, in some embodiments when the subjectprofile for the subject does not include a recent blood pressure for thesubject (e.g., a blood pressure or acknowledgement that the subject'sblood pressure is below a threshold target level that was obtained bythe device within a predetermined time period, such as within the pastmonth, within the past two months, within the past three months, withinthe past six months, within the past year, etc.), a blood pressurestatus of the subject is obtained in the second survey 210 (e.g., when asubject profile stored in the subject profile data store 232, associatedwith the subject, does not include a recent indication of the subject'sblood pressure, the device queries (810) the user to provide a bloodpressure status, e.g., actual blood pressure readings or an indicationof whether the subject's blood pressure is below a predeterminedthreshold target). In some embodiments, the predetermined time period isshorter (e.g., one month) when the user has only been authorized for asingle provision of the dihydropyridine-type calcium channel blockerpharmaceutical agent than after the user has been authorized formultiple provisions of the dihydropyridine-type calcium channel blockerpharmaceutical agent (e.g., upon the first request for re-order, theuser is prompted to provide a blood pressure status if the user'sprofile does not include a blood pressure status obtained in the pastmonth, while upon subsequent requests for re-order, the user is promptedto provide a blood pressure status if the user's profile does notinclude a blood pressure status obtained in the past six months.

Accordingly, in some embodiments, the third plurality of filters of thefirst category class 214-2 includes a second blood pressure filter thatis configured to be fired at least when the second survey resultsindicate that the subject has hypertension (e.g., a systolic bloodpressure greater than 130 mm Hg or a diastolic blood pressure greaterthan 80 mm Hg). In some embodiments, the second blood pressure filter isfired when the second survey results indicate that the systolic bloodpressure of the subject is above 130 mm Hg or the diastolic bloodpressure of the subject is above 80 mm Hg. If the blood pressure filteris fired, the subject is not permitted to obtain thedihydropyridine-type calcium channel blocker pharmaceutical compositionpharmaceutical composition over-the-counter (e.g., the method isterminated without authorizing provision of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject). Insome embodiments, the second plurality of survey results indicates thatthe subject has developed hypertension when the second plurality ofsurvey results include that the subject has been diagnosed withhypertension since receiving their last provision of thedihydropyridine-type calcium channel blocker. In some embodiments, thesecond plurality of survey results indicates that the subject hasdeveloped hypertension when the second plurality of survey resultsinclude that the subject has experienced a symptom (e.g., a new and/orworsening symptom) of hypertension since receiving their last provisionof the dihydropyridine-type calcium channel blocker.

In some embodiments, the third plurality of filters of the firstcategory class 214-2 includes a second blood pressure filter that isconfigured to be fired at least when the second survey results indicatethat the subject has hypertension (e.g., a systolic blood pressuregreater than 130 mm Hg or a diastolic blood pressure greater than 80 mmHg), regardless of whether the subject profile for the subject includesa recent blood pressure for the subject.

In some embodiments, e.g., when the second plurality of survey resultsindicate that the subject has hypertension, the device fires the secondblood pressure filter and transmits, to the subject, advice to visit adoctor to discuss taking a prescription-strength blood pressuremedication.

Referring to block 496 of FIG. 4H, the method also includes running allor a portion of the second survey results against a fourth plurality offilters of the second category class 220-2. When a respective filter inthe fourth plurality of filters is fired, the subject is provided with awarning corresponding to the respective filter. In some embodiments, thewarning is provided as a next step, e.g., prior to applying surveyresults to any subsequent filters, after the corresponding filter isfired. For example, with respect to FIGS. 8A-8B, in some embodiments,e.g., when the atherosclerotic cardiovascular event filter is triggeredat 820, the device would provide the subject with a warning prior toproceeding to the drug interaction filter at 825, e.g., requiring thesubject confirm they have discussed their atherosclerotic cardiovascularevent with a health care provider and the healthcare provider stillrecommends taking a dihydropyridine-type calcium channel blockerpharmaceutical composition. In some embodiments the warning is providedafter applying survey results to all subsequent filters. For example,with respect to FIGS. 8A-8B, in some embodiments, e.g., when theatherosclerotic cardiovascular event filter is triggered at 820, thedevice would proceed to the drug interaction filter at 825 prior totransmitting a warning to the subject, and then transmit all warningscorresponding to filters of the second category class, at 837, aftersurvey results have been applied to all subsequent filters.

Referring to block 498, in some embodiments the fourth plurality offilters comprise at least an atherosclerotic cardiovascular eventfilter, a second drug interaction filter, and a second liver diseasefilter.

In some embodiments, the fourth plurality of filters of the secondcategory class 220-2 includes some or all of the filters listed in Table6. For example, in some embodiments, the fourth plurality of filtersincludes 2, 3, or all 4 of the filters listed in Table 2.

TABLE 6 Exemplary Fourth Plurality of Filters of the Second CategoryClass Filter Exemplary Criteria 1a an atherosclerotic cardiovascularevent filter 2a a second drug interaction filter 3a a second liverdisease filter 4a a side effects filter

In one embodiment, the fourth plurality of filters includes at leastfilters 1 a-4 a as provided in Table 6. In another embodiment, thefourth plurality of filters includes at least filters 1 a, 2 a, and 3 aas provided in Table 6. In another embodiment, the fourth plurality offilters includes at least filters Ta, 2 a, and 4 a as provided in Table6. In another embodiment, the fourth plurality of filters includes atleast filters 2 a, 3 a, and 4 a as provided in Table 6. In anotherembodiment, the fourth plurality of filters includes at least filters 1a and 2 a as provided in Table 6. In another embodiment, the fourthplurality of filters includes at least filters 1 a and 3 a as providedin Table 6. In another embodiment, the fourth plurality of filtersincludes at least filters 1 a and 4 a as provided in Table 6. In anotherembodiment, the fourth plurality of filters includes at least filters 2a and 3 a as provided in Table 6. In another embodiment, the fourthplurality of filters includes at least filters 2 a and 4 a as providedin Table 6. In another embodiment, the fourth plurality of filtersincludes at least filters 3 a and 4 a as provided in Table 6.

It is contemplated that, in some embodiments, any one or more of thefilters provided in Table 6 will not be included in the fourth pluralityof filters. For example, in some embodiments, a characteristicassociated with a particular survey result will be informative whenqualifying a subject for one particular dihydropyridine-type calciumchannel blocker pharmaceutical composition but not for anotherdihydropyridine-type calcium channel blocker pharmaceutical composition.Accordingly, it is contemplated that the fourth plurality of filtersincludes any sub-set of filters provided in Table 6. Likewise, theskilled artisan may know of other filters, not provided in Table 6, thatmay be combined with any subset of the filters 222 provided in Table 6to form the fourth plurality of filters results used in the methodsdescribed herein.

Referring to block 498, in some embodiments, the fourth plurality offilters includes an atherosclerotic cardiovascular event filter that isconfigured to be fired at least when the second survey results indicatethat the subject has experienced an atherosclerotic cardiovascular eventor the subject has had a heart procedure since receiving their lastprovision of the dihydropyridine-type calcium channel blockerpharmaceutical composition. Atherosclerotic cardiovascular events,capable of firing the atherosclerotic cardiovascular event filter,include hospitalization for angina pectoris, coronary revascularization,myocardial infarction, cardiovascular death, resuscitated cardiacarrest, hospitalization for heart failure, stroke, TIA, or peripheralvascular disease. Similarly, heart procedures include pace makerinstallment, arrhythmia treatment, and aneurysm repair. In someembodiments, the second plurality of survey results indicates that thesubject has developed an atherosclerotic cardiovascular event when thesecond plurality of survey results include that the subject has beendiagnosed with an atherosclerotic cardiovascular event since receivingtheir last provision of the dihydropyridine-type calcium channelblocker. In some embodiments, the second plurality of survey resultsindicates that the subject has developed an atheroscleroticcardiovascular event when the second plurality of survey results includethat the subject has experienced a symptom (e.g., a new and/or worseningsymptom) of an atherosclerotic cardiovascular event since receivingtheir last provision of the dihydropyridine-type calcium channelblocker.

Referring to block 498, in some embodiments, the fourth plurality offilters includes a second drug interaction filter that is configured tobe fired at least when the second plurality of survey results indicatesthat the subject has started taking a medication that interacts with thedihydropyridine-type calcium channel blocker pharmaceutical compositionsince receiving their last provision of the dihydropyridine-type calciumchannel blocker pharmaceutical composition. As previously described,these interactions can be pharmacodynamic drug-drug interactions orpharmacokinetic drug-drug interactions. Typically, the interactions(e.g., triggering conditions 224) that are capable of firing the seconddrug interaction filter are the same as the interactions that arecapable of firing the first drug interaction filter assuming that thedihydropyridine-type calcium channel blocker pharmaceutical compositionis the same between the fulfillment process and the re-fulfillmentprocess.

Referring to block 498, in some embodiments, the fourth plurality offilters includes a second liver disease filter that is configured to befired at least when the second survey results indicate that the subjecthas developed symptoms of liver disease since receiving their lastprovision of the dihydropyridine-type calcium channel blockerpharmaceutical composition. In some embodiments, the second plurality ofsurvey results indicates that the subject has developed liver diseasewhen the second plurality of survey results include that the subject hasbeen diagnosed with a liver disease since receiving their last provisionof the dihydropyridine-type calcium channel blocker. In someembodiments, the second plurality of survey results indicates that thesubject has developed a liver disease when the second plurality ofsurvey results include that the subject has experienced a symptom (e.g.,a new and/or worsening symptom) of a liver disease since receiving theirlast provision of the dihydropyridine-type calcium channel blocker e.g.,hepatic enzyme elevations (e.g., which are mostly consistent withcholestasis or hepatitis, jaundice, abdominal pain and/or swelling,swelling in the legs and/or ankles, irritated skin, a dark urine color,a pale, bloody, or tar-colored stool, chronic fatigue, nausea and/orvomiting, loss of appetite, and a tendency to bruise easily.

Referring to block 500, in some embodiments the second survey resultsfurther comprise whether the subject has developed a side effectassociated with the dihydropyridine-type calcium channel blockerpharmaceutical composition since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition.Accordingly, in some embodiments, the fourth plurality of filtersfurther comprises a side effect filter that is configured to be fired atleast when the second survey results indicate that the subject hasdeveloped a side effect since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition.Side effects that are capable of triggering (e.g., triggering condition)the side effect filter include swelling of the legs, swelling of theankles, tiredness, extreme sleepiness, stomach pain, nausea, dizziness,flushing, arrhythmia or an irregular heartbeat, heart palpitations,muscle rigidity, tremors, and abnormal muscle movement. In someembodiments, side effects that are capable of triggering the side effectfilter include constipation, headache, edema, gingival overgrowth,and/or an increase or decrease in heart rate. In some embodiments, sideeffects that are capable of triggering the side effect filter includefatigue, dyspnea, tachycardia, pollakiuria, and vomiting. In someembodiments, side effects that are capable of triggering the side effectfilter mood changes (e.g., nervousness), nasal congestion, sore throat,and peripheral edema.

Referring to block 502, in some embodiments when a respective filter inthe third plurality of filters or fourth plurality of filters is fired,a record associated with the firing of the respective filter is stored(e.g., memorializing an adverse event that is required to be reported toa regulatory agency). This record is stored in an adverse event module242 which comprises records of filter firing events associated with aplurality of subjects (e.g., an aggregation of adverse events associatedwith the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition across a population of subjects taking thedihydropyridine-type calcium channel blocker pharmaceutical compositionover-the-counter). In some embodiments, an indication of the adverseevent is communicated to a third party (e.g., a medical practitionerassociated with the subject, a health care provider of the subject,and/or a manufacturer/promoter of the dihydropyridine-type calciumchannel blocker pharmaceutical composition). In some embodiments, theindication is automatically stored in the adverse event module 242 whensubmitted by a subject as part of the second survey.

Referring to block 504, in some embodiments the method also includesobtaining acknowledgment from the subject for each warning issued to thesubject by any filter in the fourth plurality of filters. As describedwith respect to the warnings issued in conjunction with the secondplurality of filters of the second category class, in some embodiments,the warning includes a prompt for the subject to indicate whether theyhave discussed the risk factor underlying the respective filter in thesecond plurality of filters that was fired with a health carepractitioner (e.g., a licensed medical practitioner), e.g., and thehealth care practitioner indicated that the subject should take adihydropyridine-type calcium channel blocker pharmaceutical compositionin view of the underlying risk factor. Accordingly, acknowledgement isobtained from the subject when the subject indicates that they havediscussed the risk factor underlying the respective filter in the fourthplurality of filters that was fired with a health care provider.

Referring to block 506 of FIG. 4I, in some embodiments the procedurefurther comprises proceeding with the re-fulfillment process when there-fulfillment process is not already terminated by the firing of afilter in the third plurality of filters (e.g., the second pregnancyfilter). In order for the re-fulfillment process to complete the subjectis required to acknowledge each warning associated with each filter222-2 in the fourth plurality of filters that was fired.

Referring to block 508, in some embodiments the re-fulfillment processalso includes storing an indication in the user profile 234 of thesubject of a re-order 238 for the dihydropyridine-type calcium channelblocker pharmaceutical composition. The re-fulfillment process furthercomprises communicating an over-the-counter drug facts label 230 for thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject. As previously described, the communication of theover-the-counter drug facts label 230 can occur in a variety of means.Upon confirmation from the subject that the over-the-counter drug factslabel 230 has been received and read, the method includes authorizing are-order provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject. In some embodiments, thisre-order provision includes the destination of the subject.

FIG. 7 illustrates an example method (700) (e.g., performed at anelectric device) for qualifying a subject for an over-the-counterdihydropyridine-type calcium channel blocker pharmaceutical composition.In some embodiments, the method of FIG. 7 is utilized when the subjecthas not been previously qualified for the medication. In someembodiments, the method of FIG. 7 is utilized when the subject waspreviously qualified for the dihydropyridine-type calcium channelblocker pharmaceutical composition but a predetermined period of timeelapsed since the previous qualification occurred (e.g., the most recentqualification of the subject was greater than one year ago).

Referring to FIG. 7 , the device prompts (702) the subject toacknowledge a privacy notice. Since the present disclosure requires thesubject to know and input sensitive medical information (e.g.,information only the subject and a medical practitioner have access to),privacy of this information is important. Once the subject hasacknowledged they have the requisite privacy for continuing, the deviceprompts (704) the user to confirm that they know their blood pressureand cholesterol levels (e.g., because the subject must know their bloodpressure and their total cholesterol, including their HDL, values inorder to complete the qualification process). If the subject indicatesthey do not know their blood pressure or cholesterol level, the processterminates 795-2 without authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical agent, andoptionally transmits advice to the user to return later, e.g., once theyknow their blood pressure and cholesterol levels. If the subjectindicates they know their blood pressure and cholesterol levels, theprocess continues.

The device prompts the subject to provide information about theirpregnancy status and then applies (705) the answer received from thesubject to a pregnancy filter. When the pregnancy filter is fired (e.g.,when the answer indicates the subject is pregnant, breastfeeding, orplanning to become pregnant), the device terminates (795-1) thequalification process without authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical agent and,optionally, transmits advice to the user as to why they should not takethe dihydropyridine-type calcium channel blocker pharmaceutical agent.

When the pregnancy filter is not fired, the device proceeds with thequalification process, prompting the subject to indicate whether theyare taking a dihydropyridine-type calcium channel blocker and thenapplies (710) the answer received from the subject to a dihydropyridinemedication filter. When the dihydropyridine medication filter is fired(e.g., when the answer indicates the subject is taking adihydropyridine-type calcium channel blocker), the device terminates(795-2) the qualification process without authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical agent and,optionally, transmits advice to the user to return later (e.g., whenthey are not taking a dihydropyridine-type calcium channel blockerpharmaceutical agent).

When the dihydropyridine medication filter is not fired, the deviceproceeds with the qualification process, prompting the subject toprovide their blood pressure and then applies (715) the answer receivedfrom the subject to a blood pressure filter. When the blood pressurefilter is fired (e.g., when the answer indicates the subject has normalblood pressure, slightly elevated blood pressure, stage 2 hypertension,or is in hypertensive crisis), the device terminates (795-3 through795-6) the qualification process without authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical agent.Optionally, when the device terminates the process in response todetermining (715-2) the subject has slightly elevated blood pressure,the device transmits (795-3) advice for the subject to maintain ahealthy diet and to exercise. Optionally, when the device terminates theprocess in response to determining (715-3) the subject has normal bloodpressure, the device transmits (795-4) advice for the subject that theydo not need a dihydropyridine-type calcium channel blockerpharmaceutical agent. Optionally, when the device terminates the processin response to determining (715-4) the subject has hypertension stage 2,the device transmits (795-5) advice for the subject to discuss obtaininga prescription for a dihydropyridine-type calcium channel blockerpharmaceutical agent with a medical professional. Optionally, when thedevice terminates the process in response to determining (715-4) thesubject is in hypertensive crisis, the device transmits (795-6) advicefor the subject to seek emergency medical care.

When the blood pressure filter is not fired, the device proceeds withthe qualification process, prompting the subject to provide informationabout their cardiovascular history. When the answer to the promptindicates the subject has had a cardiovascular problem or heartprocedure, the device creates a record of an exemption condition(760-1). The device proceeds with the qualification process, prompting(725) the subject to provide information about their gender. The deviceproceeds with the qualification process, prompting the subject toprovide their age and then applies (730) this information to an agefilter. When the age filter is fired (e.g., when the subject is lessthan eighteen years old), the device terminates (795-1) thequalification process without authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical agent and,optionally, transmits advice to the user as to why they should not takethe dihydropyridine-type calcium channel blocker pharmaceutical agent.When the subject answers that they are eighty years old or greater, thedevice creates a record of an exemption condition (760-2).

When the age filter is not fired, the device proceeds with thequalification process, prompting the subject to provide their race(735), whether they are currently taking blood pressure medication(740), whether they have diabetes (745), their history of smoking (750),and their cholesterol levels (755). If no record of an exemptioncondition was created (e.g., the subject has not had a cardiovascularproblem or heart procedure and is younger than 80), the devicecalculates an atherosclerotic cardiovascular disease (ASCVD) event riskfor the subject (e.g., based on the answers to prompts (715-755) andapplies (765) the calculated risk to a pooled cohort equation filter.When the pooled cohort equation filter is fired (e.g., when the risk ofan ASCVD event is less than 10 percent or is incalculable), the deviceterminates (795-3, 795-7) the qualification process without authorizingprovision of the dihydropyridine-type calcium channel blockerpharmaceutical agent. Optionally, when the device terminates the processin response to determining (765-2) the subject has an incalculable riskfor an ASCVD event, the device transmits (795-7) advice for the subjectto visit a medical professional to discuss whether taking adihydropyridine-type calcium channel blocker pharmaceutical agent isappropriate. Optionally, when the device terminates the process inresponse to determining (765-3) that the subject has a low risk of anASCVD event (e.g., less than 10%), the device transmits (795-3) advicefor the subject to maintain a healthy diet and to exercise.

When the pooled cohort equation filter is not fired, the device proceedswith the qualification process, prompting the subject to indicatewhether they have had liver problems and then applies (770) the answerreceived from the subject to a liver disease filter. When the liverdisease filter is fired (e.g., when the answer indicates the subject hashad a liver problem), the device initiates (780-1) an override procedure(e.g., creates a record indicating that the user must confirm they havediscussed taking a dihydropyridine-type calcium channel blockerpharmaceutical composition with a health care provider).

The device proceeds with the qualification process, prompting thesubject to provide information about their current medications (e.g.,whether they're currently taking a medication that interacts with thedihydropyridine-type calcium channel blocker pharmaceutical composition)and then applies (775) the answer received from the subject to a druginteraction filter. When the drug interaction filter is fired (e.g.,when the answer indicates the subject is taking a medication thatinteractions with the dihydropyridine-type calcium channel blockerpharmaceutical composition), the device initiates (780-2) an overrideprocedure (e.g., creates a record indicating that the user must confirmthey have discussed taking a dihydropyridine-type calcium channelblocker pharmaceutical composition with a health care provider).

The device proceeds with the qualification process, determining (782)whether the override procedure has been triggered (e.g., by firing ofeither of the liver disease or drug interaction filters). If theoverride procedure has been triggered, the device prompts (784) the userto confirm that they have spoken with a medical professional abouttaking a dihydropyridine-type calcium channel blocker pharmaceuticalcomposition (e.g., in view of the underlying risk factor that triggeredthe liver disease and/or drug interaction filter) and the medicalprofessional recommended taking the dihydropyridine-type calcium channelblocker pharmaceutical composition. If the user's response indicatesthey have not spoken with a medical professional or the medicalprofessional did not recommend taking the dihydropyridine-type calciumchannel blocker pharmaceutical composition, the device terminates(795-8) the process and, optionally, transmits advice for the subject toconsult a medical professional.

If the override procedure was not triggered, or the override procedurewas triggered and the subject's response indicated that a medicalprofessional recommended they take a dihydropyridine-type calciumchannel blocker pharmaceutical composition (e.g., in view of theunderlying risk factor triggering the override procedure), the deviceproceeds with the qualification process, prompting (785) the subject toconfirm their answers. If the user confirms their answers, the devicetransmits (790) a drug facts label for the dihydropyridine-type calciumchannel blocker pharmaceutical composition and prompts the user to readthe drug facts label. If the subject confirms they have read the drugfacts label, the device proceeds to authorize (795) purchase of thedihydropyridine-type calcium channel blocker pharmaceutical composition.

FIG. 8 illustrates an example method for qualifying a subject for arefill of an over-the-counter dihydropyridine-type calcium channelblocker pharmaceutical composition (e.g., following a prescription froma medical professional or initial qualification by a method describedherein). Referring to FIG. 8 , the device prompts (802) the subject toacknowledge a privacy notice. Once the subject has acknowledged theyhave the requisite privacy for continuing, the device determines (805)whether a blood pressure input for the subject is required. When anewblood pressure input is required (e.g., when the subject's profile doesnot include a record of the subject's blood pressure taken within thepast month, e.g., for a first reorder process, or within the past sixmonths, e.g., for a subsequent reorder process), the device prompts(810) the subject to confirm they know their blood pressure. When theuser indicates they do not know their blood pressure, the deviceterminates (895-1) the process without authorizing provision of thedihydropyridine-type calcium channel blocker pharmaceutical agent,optionally transmitting advice for the user to return once they knowtheir blood pressure. When the user indicates they do know their bloodpressure, the device proceeds with the process, prompting the user toindicate whether their blood pressure is below a threshold target level(e.g., under 130/80, evidencing the efficacy of the dihydropyridine-typecalcium channel blocker pharmaceutical agent) and applies (810) theanswer received from the subject to a blood pressure filter. When theblood pressure filter is fired (e.g., when the answer indicates thesubject has a blood pressure is not below a threshold target level,e.g., 130/80), the device terminates (895-2) the qualification process,optionally transmitting advice for the subject to discuss taking aprescription-strength dihydropyridine-type calcium channel blockerpharmaceutical agent with a medical professional.

When the blood pressure filter is not fired, or the subject's answerindicates their blood pressure is below the threshold target level, thedevice proceeds with the qualification process, prompting the subject toprovide information about their pregnancy status and then applies (815)the answer received from the subject to a pregnancy filter. When thepregnancy filter is fired (e.g., when the answer indicates the subjectis pregnant, breastfeeding, or planning to become pregnant), the devicecreates (890-1) a record of an adverse event (e.g., aggregated in anadverse event data store having records of adverse events from aplurality of users), terminates (895-3) the qualification process and,optionally, transmits advice to the user as to why they should not takethe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition.

When the pregnancy filter is not fired, the device proceeds with thequalification process, prompting the subject to provide informationabout their cardiovascular history and applies (820) the answer to anatherosclerotic cardiovascular event filter. When the atheroscleroticcardiovascular event filter is fired (e.g., when the subject's answerindicates the subject has developed a cardiovascular problem or had aheart procedure since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceuticalcomposition), the device creates (890-2) a record of an adverse event(e.g., aggregated in an adverse event data store having records ofadverse events from a plurality of users) and initiates (835-1) anoverride procedure (e.g., creates a record indicating that the user mustconfirm they have discussed taking a dihydropyridine-type calciumchannel blocker pharmaceutical composition with a health careprofessional).

The device proceeds with the qualification process, prompting thesubject to provide information about their current medications and thenapplies (825) the answer received from the subject to a drug interactionfilter. When the drug interaction filter is fired (e.g., when the answerindicates the subject has started taking a medication that interactionswith the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition), the device initiates (835-2) an override procedure (e.g.,creates a record indicating that the user must confirm they havediscussed taking a dihydropyridine-type calcium channel blockerpharmaceutical composition with a health care professional).

The device proceeds with the qualification process, prompting thesubject to indicate whether they have developed a liver problem and thenapplies (830) the answer received from the subject to a liver diseasefilter. When the liver disease filter is fired (e.g., when the answerindicates the subject has developed a liver problem since receivingtheir last provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition), the device creates (890-2) a record of anadverse event (e.g., aggregated in an adverse event data store havingrecords of adverse events from a plurality of users) and initiates(835-3) an override procedure (e.g., creates a record indicating thatthe user must confirm they have discussed taking a dihydropyridine-typecalcium channel blocker pharmaceutical composition with a health careprofessional).

The device proceeds with the qualification process, determining (835)whether the override procedure has been triggered (e.g., by firing ofany one of the atherosclerotic cardiovascular event filter, the liverdisease filter, or the drug interaction filter). If the overrideprocedure has been triggered, the device prompts (837) the user toconfirm that they have spoken with a medical professional about taking adihydropyridine-type calcium channel blocker pharmaceutical composition(e.g., in view of the underlying risk factor that triggered theatherosclerotic cardiovascular event, liver disease, and/or druginteraction filter) and the medical professional recommended taking thedihydropyridine-type calcium channel blocker pharmaceutical composition.If the user's response indicates they have not spoken with a medicalprofessional or the medical professional did not recommend taking thedihydropyridine-type calcium channel blocker pharmaceutical composition,the device terminates (895-3) the process and, optionally, transmitsadvice for the subject to consult a medical professional.

If the override procedure was not triggered, or the override procedurewas triggered and the subject's response indicated that a medicalprofessional recommended they take a dihydropyridine-type calciumchannel blocker pharmaceutical composition (e.g., in view of theunderlying risk factor triggering the override procedure), the deviceproceeds with the re-qualification process, prompting (840) the subjectto confirm their answers. If the user confirms their answers, the devicetransmits (845) a drug facts label for the dihydropyridine-type calciumchannel blocker pharmaceutical composition and prompts the user to readthe drug facts label. If the subject confirms they have read the drugfacts label, the device proceeds to authorize purchase of thedihydropyridine-type calcium channel blocker pharmaceutical composition

Specific Embodiments

In one aspect, the disclosure provides methods, software, and computersystems for qualifying a human subject for over-the-counter delivery ofa dihydropyridine-type calcium channel blocker pharmaceuticalcomposition to lower blood pressure, e.g., treating or preventing heartdisease. In one embodiment, a computer system (e.g., computer system 250in FIG. 2 ) includes instructions for conducting a survey of the subject(e.g., survey module 204 in FIG. 2 ) to obtain information about thesubject necessary to run against at least two series of filters (e.g.,first filter category class 214 in FIG. 2 and second filter categoryclass 220 in FIG. 2 ). The computer system also includes instructionsfor running the survey results against the filters. Filters 216 in thefirst series of filters prevent authorization for delivery of the OTCdihydropyridine-type calcium channel blocker where the subject's surveyresults identify a contraindication for the OTC dihydropyridine-typecalcium channel blocker. Filters 222 in the second series of filtersgenerate a warning 226 where the subject's survey results identify arisk factor for the OTC dihydropyridine-type calcium channel blocker. Insome embodiments, the warning 226 includes a prompt requiring thesubject to confirm they have discussed the risk factor with a physicianin order to proceed with qualification for the OTC dihydropyridine-typecalcium channel blocker.

In one aspect, the disclosure provides methods, software, and computersystems for qualifying a human subject for a re-order forover-the-counter delivery of a dihydropyridine-type calcium channelblocker pharmaceutical composition to lower blood pressure, e.g.,treating or preventing heart disease. In one embodiment, a computersystem includes instructions, responsive to receiving a re-order requestfrom the subject for the dihydropyridine-type calcium channel blockerpharmaceutical composition, performing a re-fulfillment procedurecomprising, for conducting a second survey of the subject to obtainsurvey results for qualifying the subject for the re-order, e.g.,associated with at least two series of filters (e.g., a third series offilters of a first category class 214-2 in FIG. 2 and fourth series offilters of a second category class 220-2 in FIG. 2 ). The computersystem also includes instructions for running the survey results againstthe filters. Filters 216 in the third series of filters preventauthorization for delivery of the OTC dihydropyridine-type calciumchannel blocker where the subject's survey results identify acontraindication for the OTC dihydropyridine-type calcium channelblocker. Filters 222 in the fourth series of filters generate a warning226 where the subject's survey results identify a risk factor for theOTC dihydropyridine-type calcium channel blocker. In some embodiments,the warning 226 includes a prompt requiring the subject to confirm theyhave discussed the risk factor with a physician in order to proceed withqualification for the OTC dihydropyridine-type calcium channel blocker.

The computer system includes instructions for proceeding with are-fulfillment process only when no filters in the third series offilters was fired and the subject acknowledged each warning associatedwith each filter in the fourth plurality of filters that was fired. Thecomputer system also includes instructions for storing an indication ina subject profile of a re-order for the dihydropyridine-type calciumchannel blocker pharmaceutical composition The computer system alsoincludes instructions for communicating an over-the-counter drug factslabel 230 for the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject and, upon confirmation thatthe over-the-counter drug facts label has been received and read,authorizing provision of the OTC dihydropyridine-type calcium channelblocker pharmaceutical composition to the subject.

In one aspect, the disclosure provides a computer system for qualifyinga human subject for over-the-counter delivery of a dihydropyridine-typecalcium channel blocker pharmaceutical composition to lower bloodpressure. The computer system comprising one or more processors and amemory, the memory comprising non-transitory instructions which, whenexecuted by the one or more processor, perform a method for qualifying ahuman subject for over-the-counter delivery of the dihydropyridine-typecalcium channel blocker pharmaceutical composition. The method includesconducting a first survey of the subject thereby obtaining a firstplurality of survey results necessary to run against a first pluralityof filters of a first category class and a second plurality of filtersof a second category class. The method then includes running all or aportion of the first plurality of survey results against a firstplurality of filters of a first category class, wherein, when arespective filter in the first plurality of filters is fired, thesubject is deemed not qualified for delivery of the dihydropyridine-typecalcium channel blocker pharmaceutical composition and the method isterminated without delivery of the dihydropyridine-type calcium channelblocker pharmaceutical composition to the subject. The method thenincludes running all or a portion of the first plurality of surveyresults against a second plurality of filters of a second categoryclass, wherein, when a respective filter in the second plurality offilters is fired, the subject is provided with a warning correspondingto the respective filter. The method also includes obtainingacknowledgment from the subject for the warning issued to the subject byany filter in the second plurality of filters. The method also includesproceeding with a fulfillment process when no filter in the firstplurality of filters has been fired and the subject has acknowledgedeach warning associated with each filter in the second plurality offilters that was fired. The fulfillment process includes: storing anindication in a subject profile of an initial order for thedihydropyridine-type calcium channel blocker pharmaceutical composition,communicating an over-the-counter drug facts label for thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject, and authorizing, upon confirmation from the subject thatthe over-the-counter drug facts label has been received and read,provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject. In some embodiments, theauthorization includes a destination associated with the subject.

In some embodiments, the first plurality of survey results includes aplurality of survey results selected from the survey results listed inTable 1. In one embodiment, the first plurality of survey resultsincludes: whether the subject is one of (i) pregnant, (ii)breastfeeding, or (iii) planning to become pregnant, whether the subjectis taking a dihydropyridine-type calcium channel blocker, a systolicblood pressure of the subject, a diastolic blood pressure of thesubject, whether the subject has ever had an atheroscleroticcardiovascular event or had a heart procedure, a gender of the subject,an age of the subject, a race of the subject, whether the subject istaking any blood pressure medications, a diabetes status of the subject,a smoking status of the subject, a total cholesterol level of thesubject, a high-density lipoprotein (HDL) cholesterol level of thesubject, whether the subject has ever had a liver problem, and whetherthe subject is taking a medication that interacts with thedihydropyridine-type calcium channel blocker pharmaceutical composition.

In some embodiments, the first plurality of filters includes a pluralityof filters selected from the filters listed in Table 2. In oneembodiment, the first plurality of filters includes a pregnancy filter,a dihydropyridine medication filter, a blood pressure filter, an agefilter, and a pooled cohort equation filter.

In some embodiments, the second plurality of filters includes aplurality of filters selected from the filters listed in Table 3. In oneembodiment, the second plurality of filters includes a liver diseasefilter and a drug interaction filter.

In some embodiments, the first and second plurality of filters includesfilters selected from the filters listed in Table 8. In someembodiments, the first plurality of filters of the first category classinclude a first sub-plurality of the filters listed in Table 8, forexample, 2, 3, 4, 5, 6, 7, or all 8 of the filters listed in Table 8,and the second plurality of filters of the first category class includea second sub-plurality of the filters listed in Table 8, which isdifferent from the first sub-plurality of filters, for example, 2, 3, 4,5, 6, 7, or all 8 of the filters listed in Table 8. In some embodiments,each of the filters in the first sub-plurality of filters is differentfrom each of the filters in the second sub-plurality of filters (e.g.,no filter listed in Table 8 is included in both the first sub-pluralityand the second sub-plurality of filters). In some embodiments, a systemfor qualifying a subject for delivery of an over-the-counterdihydropyridine-type calcium channel blocker pharmaceutical compositionincludes instructions for applying only one plurality of filters, e.g.,only filters of a single category class of filters. In some embodiments,where the method, system, or software applies a single plurality offilters, the plurality of filters includes a plurality of filtersselected from the filters listed in Table 8, e.g., at least 2, 3, 4, 5,6, 7, or all 8 of the filters listed in Table 8. In some embodiments,where a filter listed in Table 8 corresponds to a filter listed in Table2 or Table 3, a threshold level sufficient to fire the correspondingfilter listed in Table 2 or Table 3, as described in detail above, issufficient to fire the filter listed in Table 8.

TABLE 8 Exemplary Filters Filter Exemplary Criteria 1b a pregnancyfilter 2b a dihydropyridine medication filter 3b a blood pressure filter4b an age filter 5b a pooled cohort equation filter 6b a dihydropyridineallergy filter 7b a liver disease filter 8b a drug interaction filter

In one aspect, the disclosure provides methods, software, and computersystems for qualifying a human subject for a re-order forover-the-counter delivery of a dihydropyridine-type calcium channelblocker pharmaceutical composition to lower blood pressure, e.g.,treating or preventing heart disease. In one embodiment, a computersystem includes instructions, responsive to receiving a re-order requestfrom the subject for the dihydropyridine-type calcium channel blockerpharmaceutical composition, performing a re-fulfillment procedurecomprising conducting a second survey of the subject thereby obtaining asecond plurality of survey results necessary to run against a thirdplurality of filters of a first category class and a fourth plurality offilters of a second category class. The method then includes running allor a portion of the second plurality of survey results against a thirdplurality of filters of a first category class, wherein, when arespective filter in the third plurality of filters is fired, thesubject is deemed not qualified for delivery of the dihydropyridine-typecalcium channel blocker pharmaceutical composition and the method isterminated without delivery of the dihydropyridine-type calcium channelblocker pharmaceutical composition to the subject. The method thenincludes running all or a portion of the second plurality of surveyresults against a fourth plurality of filters of a second categoryclass, wherein, when a respective filter in the fourth plurality offilters is fired, the subject is provided with a warning correspondingto the respective filter. The method also includes obtainingacknowledgment from the subject for the warning issued to the subject byany filter in the fourth plurality of filters. The method also includesproceeding with a re-fulfillment process when no filter in the thirdplurality of filters has been fired and the subject has acknowledgedeach warning associated with each filter in the fourth plurality offilters that was fired. The re-fulfillment process includes: storing anindication in a subject profile of a re-order for thedihydropyridine-type calcium channel blocker pharmaceutical composition,communicating the over-the-counter drug facts label for thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject, and authorizing, upon confirmation from the subject thatthe over-the-counter drug facts label has been received and read,provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject.

In some embodiments, the third series of filters includes one or morefilters listed in Table 5. In some embodiments, the third plurality offilters includes a pregnancy filter and a blood pressure filter.

In some embodiments, the fourth series of filters includes one or morefilters listed in Table 6. In some embodiments, the fourth plurality offilters includes an atherosclerotic cardiovascular event filter, a druginteraction filter, and a liver disease filter.

In some embodiments, the third and fourth plurality of filters includesfilters selected from the filters listed in Table 9. In someembodiments, the third plurality of filters of the first category classinclude a third sub-plurality of the filters listed in Table 9, forexample, 2, 3, 4, 5, or all 6 of the filters listed in Table 9, and thefourth plurality of filters of the first category class include a fourthsub-plurality of the filters listed in Table 9, which is different fromthe third sub-plurality of filters, for example, 2, 3, 4, 5, or all 6 ofthe filters listed in Table 9. In some embodiments, each of the filtersin the third sub-plurality of filters is different from each of thefilters in the fourth sub-plurality of filters (e.g., no filter listedin Table 9 is included in both the first sub-plurality and the secondsub-plurality of filters). In some embodiments, a system for qualifyinga subject for delivery of an over-the-counter dihydropyridine-typecalcium channel blocker pharmaceutical composition includes instructionsfor applying only one plurality of filters, e.g., only filters of asingle category class of filters. In some embodiments, where the method,system, or software applies a single plurality of filters, the pluralityof filters includes a plurality of filters selected from the filterslisted in Table 9, e.g., at least 2, 3, 4, 5, or all 6 of the filterslisted in Table 9. In some embodiments, where a filter listed in Table 9corresponds to a filter listed in Table 2, Table 3, Table 5, or Table 6,a threshold level sufficient to fire the corresponding filter listed inTable 2, Table 3, Table 5, or Table 6, as described in detail above, issufficient to fire the filter listed in Table 9.

TABLE 9 Exemplary Filters Filter Exemplary Criteria 1b a pregnancyfilter 2b a blood pressure filter 3b an atherosclerotic cardiovascularevent filter 4b a drug interaction filter 5b a liver disease filter 6b aside-effect filter

In one aspect, the present disclosure provides a computer system forqualifying a human subject for over-the-counter delivery of adihydropyridine-type calcium channel blocker pharmaceutical compositionfor lowering blood pressure, the computer system comprising one or moreprocessors and a memory, the memory comprising non-transitoryinstructions which, when executed by the one or more processor, performa method comprising: a) conducting a first survey of the subject therebyobtaining a first plurality of survey results, wherein the firstplurality of survey results comprises: whether the subject is one of (i)pregnant, (ii) breastfeeding, or (iii) planning to become pregnant,whether the subject is taking a dihydropyridine-type calcium channelblocker, a systolic blood pressure of the subject, a diastolic bloodpressure of the subject, whether the subject has ever had anatherosclerotic cardiovascular event or had a heart procedure, a genderof the subject, an age of the subject, a race of the subject, whetherthe subject is taking any blood pressure medications, a diabetes statusof the subject, a smoking status of the subject, a total cholesterollevel of the subject, a high-density lipoprotein (HDL) cholesterol levelof the subject, whether the subject has ever had a liver problem, andwhether the subject is taking a medication that interacts with thedihydropyridine-type calcium channel blocker pharmaceutical composition;b) running all or a portion of the first plurality of survey resultsagainst a first plurality of filters of a first category class, wherein,when a respective filter in the first plurality of filters is fired, thesubject is deemed not qualified for delivery of the dihydropyridine-typecalcium channel blocker pharmaceutical composition and the method isterminated without delivery of the dihydropyridine-type calcium channelblocker pharmaceutical composition to the subject, wherein the firstplurality of filters comprises: a first pregnancy filter that is firedat least when the first plurality of survey results indicates that thesubject is pregnant or the subject is breastfeeding, a dihydropyridinemedication filter that is fired at least when the first plurality ofsurvey results indicates that the subject is taking adihydropyridine-type calcium channel blocker, a first blood pressurefilter that is fired at least when the first plurality of survey resultsindicates the subject has normal blood pressure or the subject hashypertension stage 2, an age filter, and a pooled cohort equation filterthat incorporates the gender of the subject, the age of the subject, therace of the subject, the blood pressure medication status of thesubject, the diabetes status of the subject, the smoking status of thesubject, the total cholesterol level of the subject, the HDL cholesterollevel of the subject, and the systolic blood pressure of the subject toderive a risk for atherosclerotic cardiovascular disease; c) running allor a portion of the first plurality of survey results against a secondplurality of filters of a second category class, wherein, when arespective filter in the second plurality of filters is fired, thesubject is provided with a warning corresponding to the respectivefilter, and wherein the second plurality of filters comprises: a firstliver disease filter that is fired at least when the first plurality ofsurvey results indicates that the subject has had a liver problem, and afirst drug interaction filter that is fired at least when the firstplurality of survey results indicates that the subject is taking amedication that interacts with the dihydropyridine-type calcium channelblocker pharmaceutical composition; d) obtaining acknowledgment from thesubject for the warning issued to the subject by any filter in thesecond plurality of filters; and e) proceeding with a fulfillmentprocess when (i) no filter in the first plurality of filters has beenfired and (ii) the subject has acknowledged each warning associated witheach filter in the second plurality of filters that was fired, whereinthe fulfillment process comprises: storing an indication in a subjectprofile of an initial order for the dihydropyridine-type calcium channelblocker pharmaceutical composition, communicating an over-the-counterdrug facts label for the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject, and authorizing, uponconfirmation from the subject that the over-the-counter drug facts labelhas been received and read, provision of the dihydropyridine-typecalcium channel blocker pharmaceutical composition to the subject.

In some embodiments of the aspects disclosed above, thedihydropyridine-type calcium channel blocker pharmaceutical compositionhas the structure:

where: Y is —(CH₂)₂—, —(CH₂)₃—, —CH₂CH(CH₃)—, or —CH₂C(CH₃)₂—; R isaryl; R¹ and R² are each independently C₁-C₄ alkyl or 2-methoxyethyl;and R³ is hydrogen, C₁-C₄ alkyl, 2-(C₁-C₄ alkoxy)ethyl,cyclopropylmethyl, benzyl, or —(CH₂)_(m)COR₄ where m is 1, 2 or 3 and R⁴is hydroxy, C₁-C₄ alkoxy or —NR⁵R⁶ where R⁵ and R⁶ are eachindependently hydrogen or C₁-C₄ alkyl; wherein aryl is phenyl; phenylsubstituted by one or two of nitro, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,hydroxy, trifluoromethyl or cyano; 1-naphthyl; or 2-naphthyl.

In some embodiments of the aspects disclosed above, thedihydropyridine-type calcium channel blocker pharmaceutical compositionincludes amlodipine or a pharmaceutically acceptable salt thereof.

In some embodiments of the aspects disclosed above, thedihydropyridine-type calcium channel blocker pharmaceutical compositionincludes amlodipine besylate.

In some embodiments of the aspects disclosed above, upon confirmationfrom the subject that the over the counter drug facts label has beenreceived and read, the subject is authorized for provision of a dosageof from 1 mg to 10 mg of the dihydropyridine-type calcium channelblocker pharmaceutical no more than once per day.

In some embodiments of the aspects disclosed above, upon confirmationfrom the subject that the over the counter drug facts label has beenreceived and read, the subject is authorized for provision of a dosageof from 2.5 mg to 5 mg of the dihydropyridine-type calcium channelblocker pharmaceutical no more than once per day.

In some embodiments of the aspects disclosed above, thedihydropyridine-type calcium channel blocker pharmaceutical compositionincludes a composition selected from the group consisting of isradipine,nifedipine, and nisoldipine.

In some embodiments of the aspects disclosed above, the first pregnancyfilter is also fired when the first plurality of survey resultsindicates that the subject is planning to become pregnant.

In some embodiments of the aspects disclosed above, the dihydropyridinemedication filter is fired when the first plurality of survey resultsindicates that the subject is taking amlodipine, isradipine,nisoldipine, or nifedipine.

In some embodiments of the aspects disclosed above, the first bloodpressure filter is fired when the first plurality of survey resultsindicates that: A) the systolic blood pressure of the subject is greaterthan a ceiling systolic pressure; B) the diastolic blood pressure of thesubject is greater than a ceiling diastolic pressure; or C) the systolicblood pressure of the subject is less than a floor systolic pressure andthe diastolic blood pressure of the subject is less than a floordiastolic pressure. In some embodiments of the aspects disclosed above,the ceiling systolic pressure is 139 mm Hg; the ceiling diastolicpressure is 89 mm Hg; the floor systolic pressure is 130 mm Hg; and thefloor diastolic pressure is 80 mm Hg.

In some embodiments of the aspects disclosed above, when the firstplurality of survey results indicate that the subject has elevated bloodpressure but is not hypertensive, the method includes: firing the firstblood pressure filter; and transmitting, to the subject, advice tomanage their blood pressure by eating healthy and exercising.

In some embodiments of the aspects disclosed above, when the firstplurality of survey results indicate that the subject has hypertensionstage two, the method includes: firing the first blood pressure filter;and transmitting, to the subject, advice to visit a doctor to discusstaking a prescription-strength blood pressure medication.

In some embodiments of the aspects disclosed above, when the firstplurality of survey results indicate that the subject is in hypertensioncrisis, the method includes: firing the first blood pressure filter; andtransmitting, to the subject, advice to seek emergency medicalattention.

In some embodiments of the aspects disclosed above, the age filter isfired when the first plurality of survey results indicates that thesubject is less than eighteen years old.

In some embodiments of the aspects disclosed above, the pooled cohortequation filter is fired when the first plurality of survey resultsindicates: A) the subject is younger than forty years old; or B) thesubject has a 10-year risk for atherosclerotic cardiovascular disease,as determined using the pooled cohort equation, that is less than 10%.

In some embodiments of the aspects disclosed above, the pooled cohortequation is implemented as a multivariable Cox proportional hazardregression.

In some embodiments of the aspects disclosed above, when the firstplurality of survey results indicate that the subject is at least 80years old, that the subject has had an atherosclerotic cardiovascularevent, or that the subject has had a heart procedure, the methodincludes bypassing the pooled cohort equation filter.

In some embodiments of the aspects disclosed above, the drug interactionfilter is fired when the first plurality of survey results indicatesthat the subject is taking a medication selected from the groupconsisting of simvastatin, cyclosporine, tacrolimus, sildenafil, and aCYP3A inhibitor.

In some embodiments of the aspects disclosed above, the first pluralityof survey results further comprises whether the subject is allergic tothe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition, and the first plurality of filters includes an adversereaction filter that is fired when the first plurality of survey resultsindicates that the subject is allergic to the dihydropyridine-typecalcium channel blocker pharmaceutical composition.

In some embodiments of the aspects disclosed above, the warningcorresponding to a respective filter in the second plurality of filterscomprises a prompt for the subject to indicate whether they havediscussed the risk factor underlying the respective filter in the secondplurality of filters that was fired with a health care provider; andacknowledgement is obtained from the subject when the subject indicatesthat they have discussed the risk factor underlying the respectivefilter in the second plurality of filters that was fired with a healthcare provider.

In some embodiments of the aspects disclosed above, the fulfillmentprocess further comprises: storing a destination associated with thesubject in the subject profile.

In some embodiments of the aspects disclosed above, the fulfillmentprocess further comprises: coordinating shipping of thedihydropyridine-type calcium channel blocker pharmaceutical compositionto a physical address associated with the subject.

In some embodiments of the aspects disclosed above, the method furthercomprises: f) responsive to receiving a re-order request from thesubject for the dihydropyridine-type calcium channel blockerpharmaceutical composition, performing a re-fulfillment procedurecomprising: (i) conducting a second survey of the subject therebyobtaining a second plurality of survey results, wherein the secondplurality of survey results comprises: whether the subject is one of (i)pregnant, (ii) breastfeeding, or (iii) planning to become pregnant,whether the subject has experienced an atherosclerotic cardiovascularevent or had a heart procedure since receiving their last provision ofthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition, whether the subject has started taking a medication thatinteracts with the dihydropyridine-type calcium channel blockerpharmaceutical composition since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition,and whether the subject has developed a liver problem since receivingtheir last provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition; (ii) running all or a portion of the secondplurality of survey results against a third plurality of filters of thefirst category class, wherein, when a respective filter in the thirdplurality of filters is fired, the subject is deemed not qualified forthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition and the re-fulfillment process is terminated withoutdelivery of the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject, wherein the third pluralityof filters comprise: a second pregnancy filter that is fired at leastwhen the second plurality of survey results indicates that the subjectis pregnant or the subject is breastfeeding; and (iii) running all or aportion of the second plurality of survey results against a fourthplurality of filters of the second category class, wherein, when arespective filter in the fourth plurality of filters is fired, thesubject is provided with a warning corresponding to the respectivefilter, and wherein the fourth plurality of filters comprises: anatherosclerotic cardiovascular event filter that is fired at least whenthe second plurality of survey results indicates that the subject hasexperienced an atherosclerotic cardiovascular event or the subject hashad a heart procedure since receiving their last provision of thedihydropyridine-type calcium channel blocker pharmaceutical composition,a second drug interaction filter that is fired at least when the secondplurality of survey results indicates that the subject has startedtaking a medication that interacts with the dihydropyridine-type calciumchannel blocker pharmaceutical composition since receiving their lastprovision of the dihydropyridine-type calcium channel blockerpharmaceutical composition, and a second liver disease filter that isfired at least when the second plurality of survey results indicatesthat the subject has developed symptoms of liver disease since receivingtheir last provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition; (iv) obtaining acknowledgment from thesubject for the warning issued to the subject by any filter in thefourth plurality of filters; (v) proceeding with the re-fulfillmentprocess when (a) the re-fulfillment process is not already terminated bythe firing of a filter in the third plurality of filters and (b) thesubject has acknowledged each warning associated with each filter in thefourth plurality of filters that was fired, wherein the re-fulfillmentprocess further comprises: storing an indication in the subject profileof a re-order for the dihydropyridine-type calcium channel blockerpharmaceutical composition, communicating the over-the-counter drugfacts label for the dihydropyridine-type calcium channel blockerpharmaceutical composition to the subject, and authorizing, uponconfirmation from the subject that the over-the-counter drug facts labelhas been received and read, a re-order provision of thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the subject.

In some embodiments of the aspects disclosed above, the re-fulfillmentprocedure further comprises, when the subject profile for the subjectdoes not include a recent blood pressure for the subject: obtaining, inthe second plurality of survey results, a blood pressure status of thesubject; and including, in the third plurality of filters of the firstcategory class, a second blood pressure filter that is fired at leastwhen the second plurality of survey results indicates that the subjecthas hypertension.

In some embodiments of the aspects disclosed above, the re-fulfillmentprocedure further comprises: obtaining, in the second plurality ofsurvey results, a blood pressure status of the subject; and including,in the third plurality of filters of the first category class, a secondblood pressure filter that is fired at least when the second pluralityof survey results indicates that the subject has hypertension.

In some embodiments of the aspects disclosed above, the second bloodpressure filter is fired when the second plurality of survey resultsindicates that: A) the systolic blood pressure of the subject is above130 mm Hg, or B) the diastolic blood pressure of the subject is above 80mm Hg.

In some embodiments of the aspects disclosed above, when the secondplurality of survey results indicates that the subject has hypertension,the method includes: firing the second blood pressure filter; andtransmitting, to the subject, advice to visit a doctor to discuss takinga prescription-strength blood pressure medication.

In some embodiments of the aspects disclosed above, the second pluralityof survey results further comprises whether the subject has developed aside effect associated with the dihydropyridine-type calcium channelblocker pharmaceutical composition since receiving their last provisionof the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition, and the fourth plurality of filters further comprises aside effect filter that is fired at least when the second plurality ofsurvey results indicates that the subject has developed, since receivingtheir last provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition, a side effect selected from the groupconsisting of swelling of the legs, swelling of the ankles, tiredness,extreme sleepiness, stomach pain, nausea, dizziness, flushing,arrhythmia, heart palpitations, muscle rigidity, tremors, and abnormalmuscle movement.

In some embodiments of the aspects disclosed above, the re-fulfillmentprocess further comprises, when a respective filter in the thirdplurality of filters or fourth plurality of filters is fired, storing arecord associated with the firing of the respective filter in an adverseevent profile comprising records of filter firing events associated witha plurality of subjects.

In some embodiments of the aspects disclosed above, the lowering bloodpressure is to treat or prevent a heart disease.

In one aspect, the disclosure provides a method for lowering bloodpressure in a subject in need thereof, the method comprising:administering a (e.g., low-dose) dihydropyridine-type calcium channelblocker pharmaceutical composition to a subject qualified forover-the-counter access to the dihydropyridine-type calcium channelblocker pharmaceutical composition. In some embodiments, the subject isqualified for the over-the-counter access to the dihydropyridine-typecalcium channel blocker pharmaceutical composition using a method,system, or computer readable medium disclosed herein.

In some embodiments, the dihydropyridine-type calcium channel blockerpharmaceutical composition comprises 3-O-ethyl 5-O-methyl2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylateor a pharmaceutically acceptable salt thereof.

In some embodiments of the aspects disclosed above, thedihydropyridine-type calcium channel blocker pharmaceutical composition(e.g., an active ingredient of the composition) has the structure:

where: Y is —(CH₂)₂—, —(CH₂)₃—, —CH₂CH(CH₃)—, or —CH₂C(CH₃)₂—; R isaryl; R¹ and R² are each independently C₁-C₄ alkyl or 2-methoxyethyl;and R³ is hydrogen, C₁-C₄ alkyl, 2-(C₁-C₄ alkoxy)ethyl,cyclopropylmethyl, benzyl, or —(CH₂)_(m)COR₄ where m is 1, 2 or 3 and R⁴is hydroxy, C₁-C₄ alkoxy or —NR⁵R⁶ where R⁵ and R⁶ are eachindependently hydrogen or C₁-C₄ alkyl; wherein aryl is phenyl; phenylsubstituted by one or two of nitro, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,hydroxy, trifluoromethyl or cyano; 1-naphthyl; or 2-naphthyl.

In some embodiments of the aspects disclosed above, thedihydropyridine-type calcium channel blocker pharmaceutical compositionincludes amlodipine or a pharmaceutically acceptable salt thereof.

In some embodiments of the aspects disclosed above, thedihydropyridine-type calcium channel blocker pharmaceutical compositionincludes amlodipine besylate.

In some embodiments of the aspects disclosed above, upon confirmationfrom the subject that the over the counter drug facts label has beenreceived and read, the subject is authorized for provision of a dosageof from 1 mg to 10 mg of amlodipine besylate per day.

In some embodiments of the aspects disclosed above, upon confirmationfrom the subject that the over the counter drug facts label has beenreceived and read, the subject is authorized for provision of a dosageof from 2.5 mg to 5 mg of amlodipine per day.

In some embodiments of the aspects disclosed above, upon confirmationfrom the subject that the over the counter drug facts label has beenreceived and read, the subject is authorized for provision of a dosageof 5 mg of amlodipine besylate per day.

In some embodiments of the aspects disclosed above, thedihydropyridine-type calcium channel blocker pharmaceutical compositionincludes a composition selected from the group consisting of isradipine,nifedipine, and nisoldipine.

In some embodiments of the aspects disclosed above, upon confirmationfrom the subject that the over the counter drug facts label has beenreceived and read, the subject is authorized for provision of a dosageof from 15 mg to 90 mg per day of nifedipine. In some embodiments, thedosage of nifedipine is of from 30 mg to 60 mg per day. In someembodiments, the dosage of nifedipine is 30 mg per day. In someembodiments, the dosage of nifedipine is 60 mg per day.

In some embodiments of the aspects disclosed above, upon confirmationfrom the subject that the over the counter drug facts label has beenreceived and read, the subject is authorized for provision of a dosageof from 1 mg to 20 mg per day of isradipine. In some embodiments, thedosage of isradipine is from 5 mg to 10 mg per day. In some embodiments,the dosage of isradipine is 5 mg per day. In some embodiments, thedosage of isradipine is 10 mg per day.

In some embodiments of the aspects disclosed above, upon confirmationfrom the subject that the over the counter drug facts label has beenreceived and read, the subject is authorized for provision of a dosageof from 8.5 mg to 17 mg of nisoldipine per day. In some embodiments, thedosage of nisoldipine is 8.5 mg per day. In some embodiments, the dosageof nisoldipine is 17 mg per day.

In some embodiments, the disclosure provides methods for lowering bloodpressure with an over the counter dihydropyridine-type calcium channelblocker pharmaceutical composition. The method includes providing afirst survey for obtaining a first information set from the human, via acomputer system having a processor programed to perform the firstsurvey, where the first information set includes information about thehuman that relates to potential risk factors and contraindications forthe dihydropyridine-type calcium channel blocker pharmaceuticalcomposition, as described herein. The method also includes applying analgorithm to the first information set, via a computer system having aprocessor programed to perform the algorithm. The algorithm runs all ora portion of the first information set against a first plurality offilters, where the human is deemed not qualified for adihydropyridine-type calcium channel blocker treatment for loweringblood pressure when a respective filter in the first plurality offilters is fired and the method is terminated without authorizingprovision of the dihydropyridine-type calcium channel blockerpharmaceutical composition to the human, where the first plurality offilters includes filters related to contraindications of thedihydropyridine-type calcium channel blocker pharmaceutical compositionas described herein. The algorithm also runs all or a portion of thefirst information set against a second plurality of filters, where, whena respective filter in the second plurality of filters is fired, thehuman is provided with a warning corresponding to the respective filter,and where the second plurality of filters includes filters related torisk factors for the dihydropyridine-type calcium channel blockerpharmaceutical composition as described herein. The algorithm alsoobtains acknowledgment from the human of the risk factor associated witheach warning issued to the human by any filter in the second pluralityof filters. In some embodiments, the acknowledgement includesconfirmation that the human has discussed the risk factor with aphysician. The algorithm proceeds with a fulfillment process when (a) nofilter in the first plurality of filters has been fired and (b) thehuman has acknowledged each warning associated with each filter in thesecond plurality of filters that was fired. The fulfillment processincludes storing an indication in a subject profile of an initial orderfor the dihydropyridine-type calcium channel blocker pharmaceuticalcomposition, communicating an over the counter drug facts label for thedihydropyridine-type calcium channel blocker pharmaceutical compositionto the human, and authorizing, upon confirmation from the subject thatthe over the counter drug facts label has been received and read,provision of the dihydropyridine-type calcium channel blockerpharmaceutical composition to the human, where the authorizationincludes a destination associated with the subject. In some embodiments,the method also includes treating the human to lower the blood pressureof the human, upon authorization of the provision e.g., by providingaccess to the dihydropyridine-type calcium channel blockerpharmaceutical composition to the human and/or by administering thedihydropyridine-type calcium channel blocker pharmaceutical compositionto lower blood pressure in the human.

Examples

Example 1: A computer system is configured for qualifying a subject forover-the-counter delivery of an amlodipine pharmaceutical composition(e.g., (RS)-3-ethyl 5-methyl2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate)to treat or prevent heart disease (e.g., by lowering blood pressure).The computer system includes instructions for conducting a survey of thesubject. The survey is utilized to obtain one or more results of:whether the subject is one of pregnant, breastfeeding, or planning tobecome pregnant, whether the subject is taking a dihydropyridine-typecalcium channel blocker including but not limited to amlodipine,nifedipine, and/or isradipine, a systolic blood pressure of the subject,a diastolic blood pressure of the subject, whether the subject has everhad an atherosclerotic cardiovascular event (e.g., heart problems) orhad a heart procedure, a gender of the subject, an age of the subject(e.g., if the subject is greater than or equal to eighteen years old), arace of the subject, whether the subject is taking any blood pressuremedications, a diabetes status of the subject, a smoking status of thesubject, a total cholesterol level of the subject, a high-densitylipoprotein (HDL) cholesterol level of the subject, whether the subjecthas ever had a liver problem, and whether the subject is taking amedication that interacts with the amlodipine pharmaceuticalcomposition.

The computer system runs survey results against a first series offilters that are each associated with a first filter category class. Thefirst filter category class is configured to prevent authorization forOTC delivery of the OTC amlodipine when the subject's survey resultsidentify a contraindication for the amlodipine. In some embodiments, thefirst series of filters includes one or more of a first pregnancyfilter, a dihydropyridine medication filter, a first blood pressurefilter, an age filter, and a pooled cohort equation filter. Thepregnancy filter is configured to ensure the subject is not pregnant,breastfeeding, or planning to become pregnant. The dihydropyridinemedication filter is configured to ensure the subject is not taking amedication that has a same mechanism of action as amlodipine. The firstblood pressure filter is configured to ensure the subject is in a needto lower blood pressure. The age filter is configured to ensure thesubject is greater than or equal to eighteen years old. Furthermore, thepooled cohort equation filter is configured to ensure the subject has acertain risk for heart disease.

The computer system runs survey results against a second series offilters that each generates a warning where the subject's survey resultsidentify a risk factor for the OTC amlodipine. In some embodiments, thesecond series of filters comprises a first liver disease filter, a firstdrug interaction filter, and an optional adverse reaction filter. Thefirst liver disease filter is configured to ensure the subject has notever had a liver problem. The first drug interaction filter isconfigured to ensure the subject is not taking a substance thatinteracts with amlodipine. Substances that interact with amlodipine, andare therefore capable of firing the first drug interaction filter,include but are not limited to a statin utilized to treat cholesterolsuch as simvastatin, an immune system medicine such as cyclosporineand/or tacrolimus, an erectile dysfunction medication such assildenafil, and a CYP3A inhibitor such as diltiazem, itraconazole, andclarithromycin.

The computer system then prompts the subject to acknowledge or denyhaving discussed these warnings with a medical professional (e.g., theirphysician or healthcare provider). The computer system then proceedswith a fulfillment process only when none of the first series of filterswas fired and the subject acknowledged that they discussed each warningissued in association with the second series of filters that was fired.

The computer system stores an indication of an initial order of the OTCamlodipine in a subject profile, and communicates an over-the-counterdrug facts label for the amlodipine pharmaceutical composition to thesubject. Upon confirmation from the subject that they have received andread the over-the-counter drug facts label, the computer systemauthorizes provision of the OTC amlodipine pharmaceutical composition tothe subject.

In some embodiments, the computer system includes instructions forconducting another survey of the subject responsive to a re-orderrequest of the amlodipine pharmaceutical composition. This survey isutilized to obtain one or more results of: whether the subject is one ofpregnant, breastfeeding, or planning to become pregnant, whether thesubject has experienced an atherosclerotic cardiovascular event or had aheart procedure since receiving their last provision of the amlodipinepharmaceutical composition, whether the subject has started taking amedication that interacts with the amlodipine pharmaceutical compositionsince receiving their last provision of the amlodipine pharmaceuticalcomposition, and whether the subject has developed a liver problem sincereceiving their last provision of the amlodipine pharmaceuticalcomposition.

The computer system runs survey results against a third series offilters that are each associated with the first filter category class.In some embodiments, the third series of filters includes one or more ofa second pregnancy filter. This pregnancy filter is fired at least whenthe second plurality of survey results indicates that the subject ispregnant or the subject is breastfeeding.

The computer system runs survey results against a fourth series offilters that each generates a warning where the subject's survey resultsidentify a risk factor for the OTC amlodipine. In some embodiments, thefourth series of filters comprises an atherosclerotic cardiovascularevent filter, a second drug interaction filter, and a second liverdisease filter. The atherosclerotic cardiovascular event filter isconfigured to be fired at least when the survey results indicates thatthe subject has experienced an atherosclerotic cardiovascular event orthe subject has had a heart procedure since receiving their lastprovision of the amlodipine pharmaceutical composition. The second druginteraction filter is configured to be fired at least when the surveyresults indicates that the subject has started taking a medication thatinteracts with the amlodipine pharmaceutical composition since receivingtheir last provision of the amlodipine pharmaceutical composition. Thesecond liver disease filter is configured to be fired at least when thesurvey results indicates that the subject has developed symptoms ofliver disease since receiving their last provision of the amlodipinepharmaceutical composition

The computer system then prompts the subject to acknowledge or denyhaving discussed these warnings with a medical professional (e.g., theirphysician or healthcare provider). The computer system then proceedswith a re-fulfillment process only when none of the third series offilters was fired the subject acknowledged that they discussed eachwarning issued in association with the fourth series of filters that wasfired.

The computer system stores an indication of a re-order of the OTCamlodipine in the subject profile, and communicates the over-the-counterdrug facts label for the amlodipine pharmaceutical composition to thesubject. Upon confirmation from the subject that they have received andread the over-the-counter drug facts label, the computer systemauthorizes provision of the OTC amlodipine pharmaceutical composition tothe subject.

Example 2: A computer system is configured for qualifying a subject forover-the-counter delivery of a nisoldipine pharmaceutical composition(e.g., isobutyl methyl2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate) totreat or prevent heart disease (e.g., by lowering blood pressure). Thecomputer system includes instructions for conducting a survey of thesubject. The survey is utilized to obtain one or more results of:whether the subject is one of pregnant, breastfeeding, or planning tobecome pregnant, whether the subject is taking a dihydropyridine-typecalcium channel blocker including but not limited to amlodipine,nifedipine, nisoldipine, and/or isradipine, a systolic blood pressure ofthe subject, a diastolic blood pressure of the subject, whether thesubject has ever had an atherosclerotic cardiovascular event (e.g.,heart problems) or had a heart procedure, a gender of the subject, anage of the subject (e.g., if the subject is greater than or equal toeighteen years old), a race of the subject, whether the subject istaking any blood pressure medications, a diabetes status of the subject,a smoking status of the subject, a total cholesterol level of thesubject, a high-density lipoprotein (HDL) cholesterol level of thesubject, whether the subject has ever had a liver problem, and whetherthe subject is taking a medication that interacts with the nisoldipinepharmaceutical composition.

The computer system runs survey results against a first series offilters that are each associated with a first filter category class. Thefirst filter category class is configured to prevent authorization forOTC delivery of the OTC nisoldipine when the subject's survey resultsidentify a contraindication for the nisoldipine. In some embodiments,the first series of filters includes one or more of a first pregnancyfilter, a dihydropyridine medication filter, a first blood pressurefilter, an age filter, and a pooled cohort equation filter. Thepregnancy filter is configured to ensure the subject is not pregnant,breastfeeding, or planning to become pregnant. The dihydropyridinemedication filter is configured to ensure the subject is not taking amedication that has a same mechanism of action as nisoldipine. The firstblood pressure filter is configured to ensure the subject is in a needto lower blood pressure. The age filter is configured to ensure thesubject is greater than or equal to eighteen years old. Furthermore, thepooled cohort equation filter is configured to ensure the subject has acertain risk for heart disease.

The computer system runs survey results against a second series offilters that each generates a warning where the subject's survey resultsidentify a risk factor for the OTC nisoldipine. In some embodiments, thesecond series of filters comprises a first liver disease filter, a firstdrug interaction filter, and an optional adverse reaction filter. Thefirst liver disease filter is configured to ensure the subject has notever had a liver problem. The first drug interaction filter isconfigured to ensure the subject is not taking a substance thatinteracts with nisoldipine.

The computer system then prompts the subject to acknowledge or denyhaving discussed these warnings with a medical professional (e.g., theirphysician or healthcare provider). The computer system then proceedswith a fulfillment process only when none of the first series of filterswas fired and the subject acknowledged that they discussed each warningissued in association with the second series of filters that was fired.

The computer system stores an indication of an initial order of the OTCnisoldipine in a subject profile, and communicates an over-the-counterdrug facts label for the nisoldipine pharmaceutical composition to thesubject. Upon confirmation from the subject that they have received andread the over-the-counter drug facts label, the computer systemauthorizes provision of the OTC nisoldipine pharmaceutical compositionto the subject.

In some embodiments, the computer system includes instructions forconducting another survey of the subject responsive to a re-orderrequest of the nisoldipine pharmaceutical composition. This survey isutilized to obtain one or more results of: whether the subject is one ofpregnant, breastfeeding, or planning to become pregnant, whether thesubject has experienced an atherosclerotic cardiovascular event or had aheart procedure since receiving their last provision of the nisoldipinepharmaceutical composition, whether the subject has started taking amedication that interacts with the nisoldipine pharmaceuticalcomposition since receiving their last provision of the nisoldipinepharmaceutical composition, and whether the subject has developed aliver problem since receiving their last provision of the nisoldipinepharmaceutical composition.

The computer system runs survey results against a third series offilters that are each associated with the first filter category class.In some embodiments, the third series of filters includes one or more ofa second pregnancy filter. This pregnancy filter is fired at least whenthe second plurality of survey results indicates that the subject ispregnant or the subject is breastfeeding.

The computer system runs survey results against a fourth series offilters that each generates a warning where the subject's survey resultsidentify a risk factor for the OTC nisoldipine. In some embodiments, thefourth series of filters comprises an atherosclerotic cardiovascularevent filter, a second drug interaction filter, and a second liverdisease filter. The atherosclerotic cardiovascular event filter isconfigured to be fired at least when the survey results indicates thatthe subject has experienced an atherosclerotic cardiovascular event orthe subject has had a heart procedure since receiving their lastprovision of the nisoldipine pharmaceutical composition. The second druginteraction filter is configured to be fired at least when the surveyresults indicates that the subject has started taking a medication thatinteracts with the nisoldipine pharmaceutical composition sincereceiving their last provision of the nisoldipine pharmaceuticalcomposition. The second liver disease filter is configured to be firedat least when the survey results indicates that the subject hasdeveloped symptoms of liver disease since receiving their last provisionof the nisoldipine pharmaceutical composition

The computer system then prompts the subject to acknowledge or denyhaving discussed these warnings with a medical professional (e.g., theirphysician or healthcare provider). The computer system then proceedswith a re-fulfillment process only when none of the third series offilters was fired the subject acknowledged that they discussed eachwarning issued in association with the fourth series of filters that wasfired.

The computer system stores an indication of a re-order of the OTCnisoldipine in the subject profile, and communicates theover-the-counter drug facts label for the nisoldipine pharmaceuticalcomposition to the subject. Upon confirmation from the subject that theyhave received and read the over-the-counter drug facts label, thecomputer system authorizes provision of the OTC nisoldipinepharmaceutical composition to the subject.

Example 3: A computer system is configured for qualifying a subject forover-the-counter delivery of an isradipine pharmaceutical composition(e.g., 3-methyl 5-propan-2-yl4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate).The computer system includes instructions for conducting a survey of thesubject. The survey is utilized to obtain one or more results of:whether the subject is one of pregnant, breastfeeding, or planning tobecome pregnant, whether the subject is taking a dihydropyridine-typecalcium channel blocker including but not limited to amlodipine,nifedipine, and/or isradipine, a systolic blood pressure of the subject,a diastolic blood pressure of the subject, whether the subject has everhad an atherosclerotic cardiovascular event (e.g., heart problems) orhad a heart procedure, a gender of the subject, an age of the subject(e.g., if the subject is greater than or equal to eighteen years old), arace of the subject, whether the subject is taking any blood pressuremedications, a diabetes status of the subject, a smoking status of thesubject, a total cholesterol level of the subject, a high-densitylipoprotein (HDL) cholesterol level of the subject, whether the subjecthas ever had a liver problem, and whether the subject is taking amedication that interacts with the isradipine pharmaceuticalcomposition.

The computer system runs survey results against a first series offilters that are each associated with a first filter category class. Thefirst filter category class is configured to prevent authorization forOTC delivery of the OTC isradipine when the subject's survey resultsidentify a contraindication for the isradipine. In some embodiments, thefirst series of filters includes one or more of a first pregnancyfilter, a dihydropyridine medication filter, a first blood pressurefilter, an age filter, and a pooled cohort equation filter. Thepregnancy filter is configured to ensure the subject is not pregnant,breastfeeding, or planning to become pregnant. The dihydropyridinemedication filter is configured to ensure the subject is not taking amedication that has a same mechanism of action as isradipine. The firstblood pressure filter is configured to ensure the subject is in a needto lower blood pressure. The age filter is configured to ensure thesubject is greater than or equal to eighteen years old. Furthermore, thepooled cohort equation filter is configured to ensure the subject has acertain risk for heart disease.

The computer system runs survey results against a second series offilters that each generates a warning where the subject's survey resultsidentify a risk factor for the OTC isradipine. In some embodiments, thesecond series of filters comprises a first liver disease filter, a firstdrug interaction filter, and an optional adverse reaction filter. Thefirst liver disease filter is configured to ensure the subject has notever had a liver problem. The first drug interaction filter isconfigured to ensure the subject is not taking a substance thatinteracts with isradipine.

The computer system then prompts the subject to acknowledge or denyhaving discussed these warnings with a medical professional (e.g., theirphysician or healthcare provider). The computer system then proceedswith a fulfillment process only when none of the first series of filterswas fired and the subject acknowledged that they discussed each warningissued in association with the second series of filters that was fired.

The computer system stores an indication of an initial order of the OTCisradipine in a subject profile, and communicates an over-the-counterdrug facts label for the isradipine pharmaceutical composition to thesubject. Upon confirmation from the subject that they have received andread the over-the-counter drug facts label, the computer systemauthorizes provision of the OTC isradipine pharmaceutical composition tothe subject.

In some embodiments, the computer system includes instructions forconducting another survey of the subject responsive to a re-orderrequest of the isradipine e pharmaceutical composition. This survey isutilized to obtain one or more results of: whether the subject is one ofpregnant, breastfeeding, or planning to become pregnant, whether thesubject has experienced an atherosclerotic cardiovascular event or had aheart procedure since receiving their last provision of the isradipinepharmaceutical composition, whether the subject has started taking amedication that interacts with the isradipine pharmaceutical compositionsince receiving their last provision of the isradipine pharmaceuticalcomposition, and whether the subject has developed a liver problem sincereceiving their last provision of the isradipine pharmaceuticalcomposition.

The computer system runs survey results against a third series offilters that are each associated with the first filter category class.In some embodiments, the third series of filters includes one or more ofa second pregnancy filter. This pregnancy filter is fired at least whenthe second plurality of survey results indicates that the subject ispregnant or the subject is breastfeeding.

The computer system runs survey results against a fourth series offilters that each generates a warning where the subject's survey resultsidentify a risk factor for the OTC isradipine. In some embodiments, thefourth series of filters comprises an atherosclerotic cardiovascularevent filter, a second drug interaction filter, and a second liverdisease filter. The atherosclerotic cardiovascular event filter isconfigured to be fired at least when the survey results indicates thatthe subject has experienced an atherosclerotic cardiovascular event orthe subject has had a heart procedure since receiving their lastprovision of the isradipine pharmaceutical composition. The second druginteraction filter is configured to be fired at least when the surveyresults indicates that the subject has started taking a medication thatinteracts with the isradipine pharmaceutical composition since receivingtheir last provision of the isradipine pharmaceutical composition. Thesecond liver disease filter is configured to be fired at least when thesurvey results indicates that the subject has developed symptoms ofliver disease since receiving their last provision of the isradipinepharmaceutical composition

The computer system then prompts the subject to acknowledge or denyhaving discussed these warnings with a medical professional (e.g., theirphysician or healthcare provider). The computer system then proceedswith a re-fulfillment process only when none of the third series offilters was fired the subject acknowledged that they discussed eachwarning issued in association with the fourth series of filters that wasfired.

The computer system stores an indication of a re-order of the OTCisradipine in the subject profile, and communicates the over-the-counterdrug facts label for the isradipine e pharmaceutical composition to thesubject. Upon confirmation from the subject that they have received andread the over-the-counter drug facts label, the computer systemauthorizes provision of the OTC isradipine pharmaceutical composition tothe subject.

Example 4: A computer system is configured for qualifying a subject forover-the-counter delivery of an nifedipine pharmaceutical composition(e.g., 3,5-dimethyl2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate) totreat or prevent heart disease (e.g., by lowering blood pressure). Thecomputer system includes instructions for conducting a survey of thesubject. The survey is utilized to obtain one or more results of:whether the subject is one of pregnant, breastfeeding, or planning tobecome pregnant, whether the subject is taking a dihydropyridine-typecalcium channel blocker including but not limited to amlodipine,nifedipine, and/or isradipine, a systolic blood pressure of the subject,a diastolic blood pressure of the subject, whether the subject has everhad an atherosclerotic cardiovascular event (e.g., heart problems) orhad a heart procedure, a gender of the subject, an age of the subject(e.g., if the subject is greater than or equal to eighteen years old), arace of the subject, whether the subject is taking any blood pressuremedications, a diabetes status of the subject, a smoking status of thesubject, a total cholesterol level of the subject, a high-densitylipoprotein (HDL) cholesterol level of the subject, whether the subjecthas ever had a liver problem, and whether the subject is taking amedication that interacts with the nifedipine pharmaceuticalcomposition.

The computer system runs survey results against a first series offilters that are each associated with a first filter category class. Thefirst filter category class is configured to prevent authorization forOTC delivery of the OTC nifedipine when the subject's survey resultsidentify a contraindication for the nifedipine. In some embodiments, thefirst series of filters includes one or more of a first pregnancyfilter, a dihydropyridine medication filter, a first blood pressurefilter, an age filter, and a pooled cohort equation filter. Thepregnancy filter is configured to ensure the subject is not pregnant,breastfeeding, or planning to become pregnant. The dihydropyridinemedication filter is configured to ensure the subject is not taking amedication that has a same mechanism of action as nifedipine. The firstblood pressure filter is configured to ensure the subject is in a needto lower blood pressure. The age filter is configured to ensure thesubject is greater than or equal to eighteen years old. Furthermore, thepooled cohort equation filter is configured to ensure the subject has acertain risk for heart disease.

The computer system runs survey results against a second series offilters that each generates a warning where the subject's survey resultsidentify a risk factor for the OTC nifedipine. In some embodiments, thesecond series of filters comprises a first liver disease filter, a firstdrug interaction filter, and an optional adverse reaction filter. Thefirst liver disease filter is configured to ensure the subject has notever had a liver problem. The first drug interaction filter isconfigured to ensure the subject is not taking a substance thatinteracts with nifedipine.

The computer system then prompts the subject to acknowledge or denyhaving discussed these warnings with a medical professional (e.g., theirphysician or healthcare provider). The computer system then proceedswith a fulfillment process only when none of the first series of filterswas fired and the subject acknowledged that they discussed each warningissued in association with the second series of filters that was fired.

The computer system stores an indication of an initial order of the OTCnifedipine in a subject profile, and communicates an over-the-counterdrug facts label for the nifedipine pharmaceutical composition to thesubject. Upon confirmation from the subject that they have received andread the over-the-counter drug facts label, the computer systemauthorizes provision of the OTC nifedipine pharmaceutical composition tothe subject.

In some embodiments, the computer system includes instructions forconducting another survey of the subject responsive to a re-orderrequest of the nifedipine pharmaceutical composition. This survey isutilized to obtain one or more results of: whether the subject is one ofpregnant, breastfeeding, or planning to become pregnant, whether thesubject has experienced an atherosclerotic cardiovascular event or had aheart procedure since receiving their last provision of the nifedipinepharmaceutical composition, whether the subject has started taking amedication that interacts with the nifedipine pharmaceutical compositionsince receiving their last provision of the nifedipine pharmaceuticalcomposition, and whether the subject has developed a liver problem sincereceiving their last provision of the nifedipine pharmaceuticalcomposition.

The computer system runs survey results against a third series offilters that are each associated with the first filter category class.In some embodiments, the third series of filters includes one or more ofa second pregnancy filter. This pregnancy filter is fired at least whenthe second plurality of survey results indicates that the subject ispregnant or the subject is breastfeeding.

The computer system runs survey results against a fourth series offilters that each generates a warning where the subject's survey resultsidentify a risk factor for the OTC nifedipine. In some embodiments, thefourth series of filters comprises an atherosclerotic cardiovascularevent filter, a second drug interaction filter, and a second liverdisease filter. The atherosclerotic cardiovascular event filter isconfigured to be fired at least when the survey results indicates thatthe subject has experienced an atherosclerotic cardiovascular event orthe subject has had a heart procedure since receiving their lastprovision of the nifedipine pharmaceutical composition. The second druginteraction filter is configured to be fired at least when the surveyresults indicates that the subject has started taking a medication thatinteracts with the nifedipine pharmaceutical composition since receivingtheir last provision of the nifedipine pharmaceutical composition. Thesecond liver disease filter is configured to be fired at least when thesurvey results indicates that the subject has developed symptoms ofliver disease since receiving their last provision of the nifedipinepharmaceutical composition

The computer system then prompts the subject to acknowledge or denyhaving discussed these warnings with a medical professional (e.g., theirphysician or healthcare provider). The computer system then proceedswith a re-fulfillment process only when none of the third series offilters was fired the subject acknowledged that they discussed eachwarning issued in association with the fourth series of filters that wasfired.

The computer system stores an indication of a re-order of the OTCnifedipine in the subject profile, and communicates the over-the-counterdrug facts label for the nifedipine pharmaceutical composition to thesubject. Upon confirmation from the subject that they have received andread the over-the-counter drug facts label, the computer systemauthorizes provision of the OTC nifedipine pharmaceutical composition tothe subject.

REFERENCES CITED AND ALTERNATIVE EMBODIMENTS

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

The present invention can be implemented as a computer program productthat comprises a computer program mechanism embedded in a non-transitorycomputer readable storage medium. For instance, the computer programproduct could contain the program modules shown in any combination ofFIGS. 1, 2, and 3 and/or described in FIG. 4 or 5 . These programmodules can be stored on a CD-ROM, DVD, magnetic disk storage product,USB key, or any other non-transitory computer readable data or programstorage product.

Many modifications and variations of this invention can be made withoutdeparting from its spirit and scope, as will be apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only. The embodiments were chosen anddescribed in order to best explain the principles of the invention andits practical applications, to thereby enable others skilled in the artto best utilize the invention and various embodiments with variousmodifications as are suited to the particular use contemplated. Theinvention is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled.

What is claimed is:
 1. A method of managing blood pressure in a humansubject who was previously qualified to receive a drug, wherein the drugis a dihydropyridine-type calcium channel blocker pharmaceuticalcomposition, the method comprising, responsive to receiving a re-orderrequest: a) obtaining an information set about the subject, via acomputer system having a processor programed to obtain the informationset, the information set comprising: whether the subject is pregnant orbreastfeeding, whether the subject has experienced an atheroscleroticcardiovascular event or had a heart procedure since receiving their lastprovision of the drug, whether the subject has started taking amedication that interacts with the drug since receiving their lastprovision of the drug, and whether the subject has developed a liverproblem since receiving their last provision of the drug; b) applying analgorithm to the information set, via a computer system having aprocessor programed to perform the algorithm, wherein the algorithm: i)runs all or a portion of the information set against a first set offilters of a first category class wherein, when a respective filter inthe first set of filters is fired, the subject is deemed not qualifiedfor treatment with the drug, and wherein the first set of filterscomprises: a pregnancy filter that is fired at least when theinformation set indicates that the subject is pregnant or the subject isbreastfeeding; ii) runs all or a portion of the information set againsta second set of filters of a second category class wherein, when arespective filter in the second set of filters is fired, the subject isprovided with a warning corresponding to the respective filter, andwherein the second set of filters comprises: an atheroscleroticcardiovascular event filter that is fired at least when the informationset indicates that the subject has experienced an atheroscleroticcardiovascular event or the subject has had a heart procedure sincereceiving their last provision of the drug, a drug interaction filterthat is fired at least when the information set indicates that thesubject has started taking a medication that interacts with the drugsince receiving their last provision of the drug, and a liver diseasefilter that is fired at least when the information set indicates thatthe subject has developed symptoms of liver disease since receivingtheir last provision of the drug; iii) obtains acknowledgment from thesubject for each warning issued to the subject by any filter in thesecond set of filters; iv) proceeds with a re-fulfillment process wheni) a filter in the first set of filters has not been fired and ii) thesubject has acknowledged each warning associated with each filter in thesecond set of filters that was fired, wherein the re-fulfilment processcomprises: storing an indication in the subject profile of a re-orderfor the drug, communicating a drug facts label for the drug, andauthorizing, upon confirmation from the subject that the drug factslabel has been received and read, a re-order provision of the drug tothe subject; and c) administering the drug to the subject afterauthorization of the re-order provision, to manage blood pressure in thesubject.
 2. The method of claim 1, wherein, when the subject profile forthe subject does not include a recent blood pressure for the subject:the information set further comprises a blood pressure status of thesubject; and the first set of filters of the first category classfurther comprises a blood pressure filter that is fired at least whenthe information set indicates that the subject is hypertensive.
 3. Themethod of claim 2, wherein the blood pressure filter is fired when theinformation set indicates that: A) the systolic blood pressure of thesubject is above 130 mm Hg, or B) the diastolic blood pressure of thesubject is above 80 mm Hg.
 4. The method of claim 2, wherein the methodfurther comprises, when the blood pressure filter is fired, transmittingadvice to the subject to visit a doctor to discuss taking aprescription-strength blood pressure medication.
 5. The method of claim1, wherein: the information set further comprises a blood pressurestatus of the subject; and the first set of filters of the firstcategory class further comprises a blood pressure filter that is firedat least when the information set indicates that the subject ishypertensive.
 6. The method of claim 5, wherein the blood pressurefilter is fired when the information set indicates that: A) the systolicblood pressure of the subject is above 130 mm Hg, or B) the diastolicblood pressure of the subject is above 80 mm Hg.
 7. The method of claim1, wherein: the information set further comprises whether the subjecthas experienced a side effect associated with the drug since receivingtheir last provision of the drug, and the second set of filters furthercomprises a side effect filter that is fired at least when the secondplurality of survey results indicates that the subject has experienced aside effect associated with the drug.
 8. The method of claim 7, whereinthe side effect is selected from the group consisting of swelling of thelegs, swelling of the ankles, tiredness, extreme sleepiness, stomachpain, nausea, dizziness, flushing, arrhythmia, heart palpitations,muscle rigidity, tremors, and abnormal muscle movement.
 9. The method ofclaim 1, wherein the re-fulfillment process further comprises, when arespective filter in the first set of filters or second set of filtersis fired, storing a record associated with the firing of the respectivefilter in an adverse event profile comprising records of filter firingevents associated with a plurality of subjects.
 10. The method of claim1, wherein the administering of the drug to the subject afterauthorization of the re-order provision to manage blood pressure in thesubject is to treat or prevent a heart disease in the subject.
 11. Themethod of claim 1, wherein the drug comprises 3-O-ethyl 5-O-methyl2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate,or a pharmaceutically acceptable salt thereof, as an active ingredient.12. The method of claim 1, wherein the drug comprises an activeingredient having the structure:

wherein: Y is —(CH₂)₂—, —(CH₂)₃—, —CH₂CH(CH₃)—, or —CH₂C(CH₃)₂— R isaryl; R¹ and R² are each independently C₁-C₄ alkyl or 2-methoxyethyl;and R³ is hydrogen, C₁-C₄ alkyl, 2—(C₁-C₄ alkoxy)ethyl,cyclopropylmethyl, benzyl, or —(CH₂)_(m)COR⁴ where m is 1, 2 or 3 and R⁴is hydroxy, C₁-C₄ alkoxy or —NR⁵R⁶ where R⁵ and R⁶ are eachindependently hydrogen or C₁-C₄ alkyl; wherein aryl is phenyl; phenylsubstituted by one or two of nitro, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,hydroxy, trifluoromethyl or cyano; 1-naphthyl; or 2-naphthyl.
 13. Themethod of claim 1, wherein the drug comprises amlodipine besylate as anactive ingredient.
 14. The method of claim 13, wherein the administeringcomprises administering to the subject the drug in the form of a dosageof from 1 mg to 10 mg per day of amlodipine besylate.
 15. The method ofclaim 13, wherein the administering comprises administering to thesubject the drug in the form of a dosage of from 2.5 mg to 5 mg per dayof amlodipine besylate.
 16. The method of claim 1, wherein the drugcomprises an active ingredient selected from the group consisting ofisradipine, nifedipine, and nisoldipine.
 17. The method of claim 16,wherein the administering comprises administering to the subject thedrug in the form of a dosage of from 15 mg to 60 mg of nifedipine perday.
 18. The method of claim 16, wherein the administering comprisesadministering to the subject the drug in the form of a dosage of from 1mg to 10 mg of isradipine per day.
 19. The method of claim 16, whereinthe administering comprises administering to the subject the drug in theform of a dosage of from 8.5 mg to 17 mg of nisoldipine per day.